Skip to main content

Traditional Chinese medicine for colorectal cancer treatment: potential targets and mechanisms of action

Abstract

Colorectal cancer (CRC) is a disease with complex pathogenesis, it is prone to metastasis, and its development involves abnormalities in multiple signaling pathways. Surgery, chemotherapy, radiotherapy, target therapy, and immunotherapy remain the main treatments for CRC, but improvement in the overall survival rate and quality of life is urgently needed. Traditional Chinese medicine (TCM) has a long history of preventing and treating CRC. It could affect CRC cell proliferation, apoptosis, cell cycle, migration, invasion, autophagy, epithelial–mesenchymal transition, angiogenesis, and chemoresistance by regulating multiple signaling pathways, such as PI3K/Akt, NF-κB, MAPK, Wnt/β-catenin, epidermal growth factor receptors, p53, TGF-β, mTOR, Hedgehog, and immunomodulatory signaling pathways. In this paper, the main signaling pathways and potential targets of TCM and its active ingredients in the treatment of CRC were systematically summarized, providing a theoretical basis for treating CRC with TCM and new ideas for further exploring the pathogenesis of CRC and developing new anti-CRC drugs.

Introduction

Colorectal cancer (CRC) is the third most common malignancy worldwide, with morbidity and mortality rates of 10% and 9.4%, respectively [1]. In the past decade, the incidence of CRC in people under 50 years of age has been increasing year by year [2]. The incidence rate of CRC is estimated to increase by about 80% worldwide by 2035 [3]. Besides, it is the second most common tumor diagnosed in women and the third in men. It is worth mentioning that the incidence and mortality rate of CRC in women are approximately 25% lower than those in men [4]. CRC has become one of the risk factors threatening public health [5]. The clinical symptoms of CRC are intestinal dysfunction, mainly including abdominal pain, abdominal distension, increased frequency of bowel movements, bowel discomfort, and rectal bleeding [6]. Since the early stage of clinical symptoms are not obvious, most patients are often in the advanced stage after diagnosis. Patients with advanced CRC may develop intestinal obstruction and other systemic symptoms (such as weight loss and anemia), and even metastasis to lymph nodes, liver, lung, bone and other sites, which eventually leads to death [7]. Therefore, the study for effective treatment has become a research hotspot.

The pathogenesis of CRC is complex and diverse, and it is influenced by the interaction and influence of risk factors, such as genetics, diet, lifestyle, and inflammatory bowel disease (IBD) [8,9,10]. A long-term diet rich in red meat and lacking in fruits and vegetables may cause an increased incidence of CRC [11]. Most CRCs arise from cancer stem cells (CSC) within the colonic epithelium, accumulating progressive genetic and epigenetic alterations. These alterations result in impaired gene expression or function, thus favoring the activation of oncogenes and the downregulation of tumor suppressor genes [12]. The pathological features of CRC involve regional lymph node and distant metastasis, accompanied by molecular markers, such as BRAF, Kirsten rat sarcoma (K-Ras), microsatellite-unstable/instability (MSI) and caudal-related homeobox 2 (CDX2) [13]. BRAF, as a proto-oncogene, is involved in encoding serine/threonine protein kinases of the mitogen-activated protein kinase (MAPK) pathway; it acts as a direct effector of RAS; and it is involved in promoting tumor growth and survival [14]. Many studies have shown that BRAF mutations (BRAF-mt) are associated with prognosis and metastasis in CRC and may be influenced by MSI status [15,16,17,18]. K-Ras protein, encoded by the proto-oncogene k-RAS, is an important component of the MAPK pathway [19]. K-RAS mutation (KRAS-mt) confers tumor cell growth at lower glucose concentrations than those required by normal cells and strongly promotes tumor cell growth [20]. CDX2 encodes transcription factors involved in regulating intestinal differentiation and development [21]. It also acts as a tumor suppressor, and it is associated with the pathogenesis of distal colon tumors [22, 23].

Currently, surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy are the main treatments for CRC, but problems, such as surgical sequelae, chemotherapy resistance, toxic side effects, high metastasis, and recurrence rates, seriously affect the quality of life of patients [24, 25]. Traditional Chinese medicine (TCM), as a predominant source of natural medicines and herbal products, are essential sources for exploiting anti-CRC drugs [26]. As one of the effective means to treat CRC, TCM could exert anti-CRC effects in multiple targets and pathways while ameliorating the toxic side effects elicited by surgery chemotherapy, radiotherapy, target therapy, and immunotherapy and prolonging patients’ survival time [27, 28]. Experimental studies have shown that TCM and its components could effectively inhibit CRC cell proliferation, induce apoptosis, block cell cycle, promote cell autophagy, and inhibit angiogenesis; it also plays an anti-CRC role in cooperation radiotherapy and chemotherapy [29,30,31,32]. Regulating signaling pathways is one of the important mechanisms for CRC treatment. Exploring the mechanism of CRC-related signaling pathways could help further clarify the anti-CRC targets of TCM. Therefore, in this study, the research progress of the regulation of CRC-related signaling pathways by TCM and its active ingredients was systematically summarized, providing a reference for further studies on the prevention and treatment of CRC by TCM.

Phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) signaling pathway

The PI3K/Akt signaling pathway is one of the important intracellular signaling pathways and a major effector downstream of receptor tyrosine kinases (RTKs) and G protein coupled receptors [33, 34]. This pathway is stimulated by various oncogenes and growth factor receptors, including platelet-derived growth factor receptors, insulin like growth factor receptors, and epidermal growth factor receptors (EGFRs) [35]. The main proteins of this signaling pathway are PI3K and Akt [36]. Activation of PI3K promotes signal transduction cascades for tumor cell growth, survival, and metabolism [37]. Akt, as a serine-threonine kinase, is a major downstream target of PI3K, and it could directly respond to PI3K activation [38]. Akt/PKB kinase has three highly homologous isoforms: Akt1/PKBa, Akt2/PKBb, and Akt3/PKBg. Akt1 is involved in the regulation of tumor growth, tumor cell invasion, and chemoresistance, and it is the main isoform found in various cancers. Alterations in Akt2 could be observed in breast cancer, ovarian cancer, pancreatic cancer, and CRC, and it is associated with tumor cell invasion, metastasis, and survival. Akt3 is mainly expressed in melanoma, glioma, and some breast cancers, affecting tumor growth and drug resistance [39]. Several studies have demonstrated that the PI3K/Akt signaling pathway is aberrantly activated in many cancers, and that it is closely related to tumor cell proliferation, apoptosis, invasion, epithelial–mesenchymal transition (EMT), stem cell-like phenotype, and tumor drug resistance [40], in addition to being involved in tumor angiogenesis [41]. Therefore, targeting the PI3K/Akt signaling pathway could contribute to anti-CRC therapy (Fig. 1).

Fig. 1
figure 1

The active compounds of TCM and the Chinese herb formula act on the PI3K/Akt signaling pathway. GOD gegen qinlian decoction, TNSEs tounong powder, JSD, jiedu sangen decoction. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Wogonin (WOG) is a flavonoid compound found in Scutellaria baicalensis Georgi (Huang Qin), which has been proven to inhibit tumor cell growth and induce apoptosis [42, 43]. The expression of light chain 3-II (LC3II); Beclin-1; caspase-3, -8, and -9; and Bcl-2-associated X (Bax) protein was upregulated, whereas that of B-cell lymphoma-2 (Bcl-2) was downregulated in WOG-treated SW48 cells. Cell cycle was also arrested in the G2/M phase. In addition, the expression of p-PI3K, p-Akt, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in SW48 cells showed a concentration-dependent decrease while the expression of total PI3K, Akt and STAT3 was not significantly affected. The above results suggested that WOG may induce apoptosis and arrest cell cycle in SW48 cells through PI3K/Akt pathway[44]. Coptisine (COP), the main active ingredient in Rhizoma coptidis (Huang Lian), has antitumor activity [45, 46]. Huang et al. [47] found that COP initiated extrinsic apoptotic pathways in vitro by inhibiting the PI3K/Akt signaling pathway and thus upregulation of cleaved caspase-8 and  -3. Meanwhile, the expression levels of Cyclin D1 and Cyclin E were down-regulated, thus inducing G0/G1 phase cell cycle arrest. In HCT-116 CRC xenograft mice model, COP was found to inhibit tumor growth and effectively reverse the elevated serum markers carcinoembryonic antigen, carbohydrate antigen 19-9, and cytokeratin fragment antigen 21-1 in BALB/c nude mice. Emodin (EMD) is the main component of Rheum palmatum (Da Huang), which has been widely used in the treatment of various diseases [48]. Dai et al. [49] found that EMD inhibited the expression of VEGFR2, PI3K and p-Akt in HCT-116 cells and tumor-bearing mice, suggesting that EMD may inhibit human CRC cell growth, adhesion and migration by suppressing VEGFR2/PI3K/Akt signaling pathway. In addition, Liu et al. [50] showed that triptolide (TP), an extract of Tripterygium wilfordii Hook F. (Lei Gong Teng), could reduce the phosphorylation of p-Akt (Thr308) in HT29 cells and p-Akt (Ser473) in SW480 cells and exert anti-proliferative effects through the Akt signaling pathway Platycodin D (PD) is a triterpenoid saponin-like ingredient from the Chinese herb Platycodon grandiflorum (Jie Geng) with multiple biological effects [51,52,53]. Liu et al. [54] found that the combination of PD and cetuximab downregulated the phosphorylation of PI3K and Akt in HCT116 and LoVo cells both in vivo and in vitro, and increased the cytotoxic effect of cetuximab. The synergistic effect between PD and cetuximab was attenuated after application of Akt activator SC-79. The results mentioned above implied that PD may cause CRC cells to become more sensitive to cetuximab by inhibiting the PI3K/Akt signaling pathway. (Fig. 1).

Li et al. [55] found that Gegen Qinlian Decoction (GQD) could inhibit CT-26 CRC growth accompanied by upregulation of p-PI3K, p-Akt, phosphorylated forkhead box transcription factor O1 (p-FOXO1), and ankyrin repeat and BTB/POZ domain containing protein 1 (ABTB1). Fang et al. [56] found that Tounong powder extracts (TNSEs) induced LoVo cell growth inhibition in a dose- and time-dependent manner; significantly downregulated the expression of PI3K, p-AKT, phosphorylated mechanistic target of rapamycin (p-mTOR), and p-p70s6k1; and upregulated the expression of cleaved caspase-9 and -3. These findings suggested that TNSEs may inhibit LoVo cells through the PI3K/Akt signaling pathway. Sun et al. [57] found that the expression of hypoxia-inducible factor-1α (HIF-1α), PI3K, Akt/p-Akt, hexokinase II, and glucose transporter type 1 (GLUT1) was downregulated and that of caspase-3 and -9 was upregulated in 5-FU-resistant human CRC cells (HCT-8/5-FU) after the intervention of Jiedu Sangen decoction (JSD). HIF-1α silencing showed a significant decrease in the expression levels of PI3K, Akt, and p-Akt, accompanied by an upregulation of caspase-6 and -7 expression. This finding suggested that JSD inhibits glycolysis through the PI3K/Akt/HIF-1α signaling pathway to reverse 5-FU resistance and induce apoptosis to enhance antitumor activity (Fig. 1).

Nuclear factor kappa-beta (NF-κB) signaling pathway

NF-κB is a ubiquitous transcription factor that could directly participate in mediating cyclotomic/neutral signaling and regulate the expression of various cytokines and cell adhesion molecules involved in inflammation and immune responses [58, 59]. The activation of NF-κB correlates with apoptosis, cell cycle, proliferation, differentiation, migration, and resistance to radiation/chemotherapy in tumor cells [60]. The five currently known members of the NF-κB family are as follows: p50/p105 (NF-κB1), p52/p100 (NF-κB2), c-Rel, RelB, and p65 (RelA); each protein has its Rel homologous structural domain that controls DNA binding, dimerization, and interaction with the repressor IκB [61]. In most quiescent cells, the IκB in the cytoplasm binds to NF-κB and inactivates it by overriding the nuclear localization sequence to block DNA binding and nuclear uptake [58]. The IκB kinase (IKK) complex contains a regulatory subunit IKKγ (NEMO), catalytic subunits IKKα and IKKβ, which are upregulated by the interaction of cell surface receptors, such as Toll-like receptor, T/B cell receptor, and tumor necrosis factor receptor with specific ligands [62]. IKK could cause IκB phosphorylation via ubiquitin-proteasome pathway degradation to activate NF-κB and cause nuclear translocation [63]. In the nucleus, NF-κB binds to the enhancer elements of the immunoglobulin kappa light chain (κB sites) in activated B cells, triggering the expression of downstream genes that lead to the progression of inflammation or cancer [64, 65]. In human CRC adenocarcinoma, NF-κB expression is proportional to the abnormal activity of K-Ras [66]. The activation of NF-κB was found to be decreased in SW620 cells after K-Ras knockdown, possibly through the Ras/extracellular signal-regulated kinase (ERK)/IκBα signaling pathway [67] (Fig. 2).

Fig. 2
figure 2

The active compounds of TCM and the Chinese herb formula act on the NF/κB signaling pathway. WMW Wu Mei Wan, ZJW Zuo Jin Wan. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Oridonin (ORI) is a bioactive ingredient extracted from Rabdosia rubescens (Dong Ling Cao) [68]. It has been shown to have a therapeutic effect on various malignancies, including liver cancer, skin carcinoma, and osteoma [69, 70]. Jin et al. [71] found that the expression of HECT and RCC1-containing protein 5 was upregulated in LoVo and SW480 cells, whereas activating protein-1 (AP-1), NF-κB, and p38 were downregulated after ORI treatment. In-vivo studies confirmed that ORI first inhibited the expression of AP-1 and then downregulated the expression of p38 and NF-κB, suggesting that ORI may exert anti-CRC effects through the NF-κB signaling pathway and P38-dependent MAPK signaling pathway. Baicalein (BE) is one of the four major flavonoids found in Scutellaria baicalensis Georgi (Huang Qin), which has anti-inflammatory and anti-cancer effects [72]. Kim et al. [73] found that BE could inhibit the NF-κB signaling pathway and regulate apoptosis, migration, invasion, and inflammatory response in CRC cells through activation of peroxisome proliferator-activated receptor γ. Berberine (BBR) is a compound widely found in Chinese herbs, such as Coptidis Rhizoma (Huang Lian), Phellodendron chinense Schneid. (Huang Bai), and Berberis silva-taroucana Schneid. (Xiao Bo). Chen et al. [74] found that BBR reversed the upregulated protein expression of Ki-67 and β-catenin; downregulated the expression of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), NF-κB, matrix metallopeptidase 9 (MMP9), Ereg, and Muc16 in AMO/DSS model mice; and regulated cell proliferation, angiogenesis, and invasion through the NF-κB signaling pathway by exerting anti-CRC effects. Curcumin, the major component of Curcuma longa L. (Jiang Huang), can inhibit the proliferation of CRC cell lines and enhance capecitabine-induced apoptosis in vitro. It also inhibited the expression of NF-κB and its regulated gene products cyclo-oxygenase-2 (COX2), Cyclin D1, c-Myc, MMP-9, intercellular adhesion molecule-1 (ICAM-1), C-X-C motif chemokine receptor 4 (CXCR4), Survivin, Bcl-2 and vascular endothelial growth factor (VEGF). In vivo studies showed that curcumin was able to inhibit the growth and distal metastasis of HCT-116 CRC, and this inhibition was enhanced when combined with capecitabine. According to the aforementioned findings, curcumin may increase capecitabine’s anti-proliferative, invasive, metastatic, angiogenic, and pro-apoptotic actions on CRC via suppressing the NF-κB signaling pathway [75]. (Fig. 2).

In addition, herbal compounds may exert anti-CRC effects through the NF-κB pathway. Wu Mei Wan (WMW) is a herbal compound commonly used in clinical practice for the treatment of febrile diseases and other gastrointestinal related diseases [76]. Jiang et al. [77] found that AOM/DSS-induced colitis-associated CRC (CAC) mice showed downregulation of p65 and p-STAT3 expression in colonic tissues and downregulation of interleukin 6 (IL-6), p65, and p-STAT3 expression in serum after WMW intervention. This finding suggested that WMW inhibited tumor cell proliferation and improved CAC symptoms in model mice through downregulation of the NF-κB/IL-6/STAT pathway. Zuo Jin Wan (ZJW) consists of Coptidis Rhizoma (Huang Lian) and Evodia rutaecarpa (Juss.) Benth. (Wu Zhu Wu) in a 6:1 ratio. Sui et al. [78] found that ZJW could downregulate the phosphorylation of Akt (Ser473) and NF-κB expression in HCT-116/L-OHP cells. Moreover, the above downregulation was attenuated after treatment with PI3K/Akt activator, suggesting that ZJW reverses drug resistance in human CRC cells by blocking the PI3K/Akt/NF-κB signaling pathway and enhances the anti-apoptotic effect of oxaliplatin (Fig. 2).

Mitogen-activated protein kinase (MAPK) signaling pathway

MAPKs are serine-threonine kinases that could link extracellular signals to regulate cellular activities, such as cell proliferation, differentiation, migration, and apoptosis [79, 80]. The mammalian MAPK family includes ERK1/2; ERK3/4; ERK5; ERK7/8; Jun N-terminal kinase (JNK)1/2/3; and p38-α, -β, -γ, and -δ [81]. Each signal transduction axis of MAPK contains three components: MAPK, MAPK kinase (MAP2K), and MAPK kinase-kinase (MAP3K), which are named in accordance with their proximity to the nucleus [82]. Activation of MAPK could regulate transcription factors, such as ETS like-1 protein, c-Jun, transcription factor 2 (ATF2), and p53 [83]. The activation of MAPK pathway is the result of interactions between the kinase components [84]. In the MAPK/ERK pathway, phosphorylation of Raf (Raf-1, B-Raf, and A-Raf) activates MEK1/2, which leads to phosphorylation of ERK1/2 [79]. ERK1/2 shuttles from the cytoplasm to the nucleus and regulates gene expression by phosphorylating many transcription factors; the microtubule-associated proteins (MAP1, MAP2, and MAP4) in the cytoplasm are also targets of ERK1/2 kinases [85]. MEK and ERK1/2 are involved in cell survival, proliferation, and differentiation depending on their phosphorylated targets [86]. Activation of ERK/MAPK signaling pathway could promote tumor cell invasion and metastasis through upregulation of MMP expression [87]. JNK and p38 signaling pathways are activated by pro-inflammatory cytokines, such as TNF-α and IL-1β, or are involved in response to cellular stress [88]. MKK4 and MKK7, as representatives of MAP2K kinases, are JNK sub-pathways that are activated when MAP2K is triggered. Phosphorylation of these components activates JNK, which, in turn, phosphorylates AP-1 transcription factors, such as c-Jun, Fos, and Fos-related antigen1/2 (FRA1/2) [85]. AP-1 is associated with cell proliferation, survival, differentiation, inflammation, migration, and metastatic activities. Other downstream targets of JNK include the mitochondrial apoptosis regulator Bcl-2 family (Bcl-2, Bcl-xl, Bad, Bim, and Bax) and tumor suppressor p53, which are involved in the pro-apoptotic function of JNK [89]. In addition, JNK could promote cancer invasion and metastasis by promoting the expression of MMP7 and MMP9 [90]. The MAPK signaling pathway is an important regulator of tumor cell response to internal and external environmental stimuli. Therefore, modulation of the MAPK signaling pathway could help treat CRC (Fig. 3).

Fig. 3
figure 3

The active compounds of TCM and the Chinese herb formula act on the MAPK signaling pathway. YQFS Yi-Qi-Fu-Sheng, QZC Qizhen capsule, GJD Geijigajakyak decoction. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Ginsenoside Rh1 (Rh1), a compound of Panax ginseng C.A. Mey (Ren Shen)., has significant antitumor activity against human hepatocellular carcinoma, THP-1 acute monocytic leukemia cells, and astroglioma [91,92,93]. Lyu et al. [94] found that the expression of MMP1 and MMP3 was downregulated; the expression of tissue inhibitor of metalloproteinase 3 was upregulated; and the ratios of p-P38/P38, p-ERK1/2/ERK1-2, and p-JNK/JNK were decreased in SW620 cells after Rh1 intervention. They also showed the same trend in xenograft tumor-bearing mice, suggesting that Rh1 could exert anti-CRC effects through the MAPK signaling pathway. Diterpenoid C is an ingredient of Curcuma longa L. (Jiang Huang) [95]. Shen et al. [96] found that diterpenoid C inhibited the phosphorylation of ERK, JNK, and p38 MAPK and promoted the cleavage of caspase-3 in SW620 cells, suggesting that diterpenoid C exerts antiproliferative and pro-apoptotic effects through the MAPK signaling pathway. Podophyllotoxin (PT) is an active ingredient extracted from Podophyllum peltatum (Gui Jiu), which is highly cytotoxic to various cancer cells [97,98,99]. Lee et al. [100] found that PT intervention increased the level of reactive oxygen species (ROS), upregulated the expression of ER stress markers GRP78 and CHOP, and increased the phosphorylation of p38 MAPK in HCT-116 cells, suggesting that PT could induce the p38 MAPK signaling pathway and ER stress-mediated apoptosis through upregulation of ROS in HCT-116 cells, accompanied by G2/M phase cell-cycle arrest (Fig. 3).

In addition, Deng et al. [101] found that the Chinese herbal formula Yi-Qi-Fu-Sheng (YQFS) exerted anti-CRC effects in vivo and in vitro. In vivo, YQFS significantly inhibited tumor growth by downregulating the expression of MMP2 and MMP9 through inhibiting the ERK pathway. In vitro, YQFS inhibited HCT-116 cell invasion and migration and induced apoptosis by targeting ERK phosphorylation to regulate the ERK/MAPK pathway and its downstream factors. Guo et al. [102] found that Qizhen capsule (QZC), a commonly used clinical anticancer agent, could upregulate the levels of cleaved caspase-9 and -3, Bax, and nonsteroidal anti-inflammatory drug-activated gene-1/growth differentiation factor-15 (NAG-1/GDF15) and the phosphorylated expression of mTOR, MAPK/ERK, AMP-activated protein kinase (AMPK), and p38 and downregulate the expression of Bcl-2. QZC could exert a pro-apoptotic effect on HCT-116 cells by activating the MAPK/ERK signaling pathway mediating the upregulation of NAG-1/GDF15. Lee et al. [103] found that the expression of p-JNK and p-p38 MAPK was downregulated in HCT-116 cells after Geijigajakyak decoction (GJD) intervention, suggesting that GJD plays a role in anti-CRC invasion through JNK and p38 MAPK signaling pathways (Fig. 3).

Wnt/β-catenin signaling pathway

The Wnt signaling pathway could be divided into canonical (β-catenin-dependent activity) and non-canonical (β-catenin-independent activity) Wnt pathways [104]. The β-catenin-dependent signaling pathway is mainly involved in the regulation of cell proliferation, and the β-catenin-independent signaling pathway is associated with cell mobility and polarity [105, 106]. The canonical Wnt/β-catenin pathways involve several interacting proteins, including the serine/threonine kinases glycogen synthase kinase 3beta (GSK3β) and casein kinase 1 (CK1), the tumor suppressors Axin and adenomatous polyposis coli (APC), and the E3 ubiquitin ligase β-TrCP, together forming the destruction complex; Axin is the backbone of the complex, interacting with β-catenin, GSK3β, and CK1 [107]. Activation of canonical Wnt/β-catenin pathways allows β-catenin to accumulate in the cytoplasm and further translocate to the nucleus as a transcriptional co-activator of T-cell transcription factor (TCF)/lymphoid enhancer factor (LEF) [108, 109]. The activity of Wnt/β-catenin signaling is related to the level of β-catenin in the nucleus, and regulation of the level of β-catenin is the basis of controlling the Wnt/β-catenin signaling pathway [110]. β-catenin binds to its transcription factors and causes transcription of target genes, such as c-Myc, cyclin D1, and MMPs [111]. Aberrant activation of the Wnt/β-catenin signaling pathway contributes to cell proliferation, differentiation, and renewal of tumor stem cells [112]. In most CRCs, overexpression of target genes in the Wnt/β-catenin signaling pathway induces dysregulation of the CRC cell cycle, along with accelerated invasion and metastasis [113, 114]. Regulation of the Wnt/β-catenin signaling pathway contributes to anti-CRC proliferation and metastasis effects (Fig. 4).

Fig. 4
figure 4

The active compounds of TCM and the Chinese herb formula act on the Wnt/β-catenin signaling pathway. WCA Weichang’an, ZJW Zuo Jin Wan, PNS Pai-Nong-San. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Several studies have confirmed that emodin induces apoptosis and inhibits the migration and invasion of colon cancer cells [115, 116]. Pooja et al. [117] showed that emodin significantly inhibited the mRNA expression of CTNNB1 (β-catenin) and transcription factor-7-like-2 (TCF7L2) and the expression of cyclin D1, c-Myc, snail, vimentin, MMP2, and MMP9, the downstream targets of Wnt signaling in human colon cancer cells. Further investigation of the inhibitory mechanism of emodin on Wnt signaling revealed that emodin downregulated coactivator p300 and upregulated transcriptional repressor HBP1 at the mRNA and protein levels, suggesting that emodin exerts anti-CRC effects by inhibiting the Wnt signaling pathway. Ginkgolide C (GGC) is a diterpenoid lactone compound isolated from Ginkgo biloba L. (Yin Xing Ye) [118, 119]. Yang et al. [120] found that GGC downregulated the Wnt/β-catenin signaling cascade and the expression of MMP2, MMP9, Wnt3a, β-catenin, and β-catenin downstream signals (Axin-1, p-GSK3β, and β-TrCP) and their target genes (c-myc, cyclin D1, and survivin) in HT-29 cells, suggesting that GGC may play a role in the anti-proliferation, anti-invasion, anti-migration and pro-apoptosis of CRC cells by targeting the Wnt/β-catenin signaling pathway. Curcumin, the main component of Curcuma longa L. (Jiang Huang), has also shown antitumor activity [121,122,123]. Jiang et al. [124] found that curcumin could significantly upregulate the expression of CDX2; downregulate the expression of Wnt3a and Wnt downstream signaling genes, such as c-Myc, surviving, and cyclin D1; and decrease the nuclear translocation of β-catenin in SW620 cells. After silencing the CDX2, the inhibitory effects of curcumin on c-Myc, surviving, and cyclin D1 were significantly reduced. These results suggested that curcumin inhibits the Wnt/β-catenin signaling pathway by activating CDX2 and then exerts anti-proliferative and pro-apoptotic effects on SW620 cells. In addition, baicalein, the active ingredient in Scutellaria baicalensis Georgi, alleviates oxaliplatin-induced peripheral neuropathy, possibly also through the Wnt/β-catenin signaling pathway [125] (Fig. 4).

Tao et al. [126] found that the Chinese herbal formula Weichang’an (WCA) dose-dependently upregulated rho GTPase activating protein 25 (ARHGAP25) expression in HCT-116 cells while downregulating the expression of MMP7, MMP9, zinc finger E-box binding homeobox 1 (ZEB1), and β-catenin, suggesting that inhibition of the Wnt/β-catenin signaling pathway is the mechanism by which WCA exerts its anti-CRC migratory and invasive effects in vitro. Pan et al. [127] found that the expression of 5-hydroxytryptamine receptor D (5-HTR1D) and axin-1 was dose-dependently increased, whereas that of dishevelled 2 (Dvl2), p-GSK-3β, lymphoid enhancer-binding factor 1 (LEF1), transcription factor 4 (TCF4), MMP2, MMP7, ICAM-1, and CXCR4 was dose-dependently decreased in SW408 cells treated with Zuo Jin Wan (ZJW) extract. This finding indicated that the anti-CRC activity of ZJW extract could be achieved by inhibiting the 5-HTR1D-Wnt/β-catenin signaling pathway. In addition, Zhang et al. [128] found that Pai-Nong-San (PNS) was protective against AOM/DSS-induced colonic injury and able to downregulate p-GSK3β, β-catenin, and c-Myc while upregulating GSK3β and p-β-catenin. These results suggested that PNS could suppress inflammation, improve intestinal microbiota, and inhibit the Wnt signaling pathway to inhibit CRC development (Fig. 4) .

EGFR signaling pathway

The EGFR family is composed of four related domains, namely, the extracellular ligand-binding domain, the hydrodynamic transmembrane region, the intracellular RTK domain, and the C-terminal domain, which could assist in participating in a series of physiological activities related to epithelial cells [129,130,131,132,133]. Multiple ligands, including EGF, bind to the receptor and induce its dimerization, thereby activating tyrosine kinase (TK) and multiple downstream effectors [134]. Many ligands, such as am-phiregulin (AR), betacellulin, epidermal growth factor (EGF), heparin-binding EGF-like growth factor, and transforming growth factor α (TGF-α) could activate EGFR [134, 135]. The EGFR phosphorylation response is activated and then signals to downstream pathways, such as the Ras/MAPK pathway, the PI3K/Akt pathway, and the phospholipase C/protein kinase C signaling cascade, which ultimately participate in various cellular activities such as cell survival, proliferation, differentiation, motility, and apoptosis [136, 137]. EGFR and other family members are overexpressed or amplified in cancer, causing uncontrolled proliferation of tumor cells. The receptors are internalized and disrupted upon activation, attenuating the signal or cycling to the outer membrane, resulting in persistent signaling [132, 133]. EGFR is overexpressed in most solid tumors, such as non-small cell lung cancer, head and neck squamous cell carcinoma, CRC, and breast cancer [138,139,140]. Such tumors are aggressive, drug resistant, and rapidly growing. Therefore, targeting EGFR is one of the directions to develop and design anti-cancer drugs. Currently, the EGFR inhibitors cetuximab and pantitumumab are clinically used to treat mCRC [141, 142] (Fig. 5).

Fig. 5
figure 5

The active compounds of TCM act on the EGFR signaling pathway. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

8-Gingerol is one of the main active ingredients of Zingiber officinale Rosc (Sheng Jiang) [143]. Hu et al. [144] found that the phosphorylation levels of EGFR and its downstream effectors STAT3 and ERK were reduced in HCT-166 and DLD1 cells after 8-gingerol treatment, which, in turn, led to the downregulation of the expression of target genes, cyclin D1, c-Myc, and MMP2. Meanwhile, the addition of EGF could restore the above phosphorylation levels and protein expression, suggesting that 8-gingerol exerts its anti-proliferative and migratory effects on CRC cells through the EGFR/STAT/ERK signaling pathway. Gambogic acid (GA) is an active component extracted from Gamboge hanburyi (Teng Huang), which has been proven to have antitumor effects in many tumors [145,146,147]. Wei et al. [148] found that the expression of stemness-related genes, such as Nanog, octamer-binding transcription factor 4, SRY-box transcription factor 2 (SOX2), aldehyde dehydrogenase 1, cluster of differentiation 133 (CD133), and B-lymphoma Mo-MLV insertion region 1 (Bmi-1), were significantly reduced in CRC cell lines after GA intervention. The protein expression of its downstream gene zinc-finger protein 36 (ZFP36) was enhanced by inhibiting the phosphorylated expression of EGFR and ERK. The findings suggested that GA could reduce stemness-related genes in CRC cells and exert inhibitory effects on CRC stem cells by suppressing the activation of the EGFR/ERK/ZFP36 signaling pathway. Norcantharidin (NCTD) is an active ingredient isolated and demethylated from Mylabris phalerata Pall (Ban Mao), which has significant antitumor activity [149]. Qiu et al. [150] found that NCTD inhibited the expression of EGFR, human epidermal growth factor receptor-2, and c-MET factor and their phosphorylation in HCT-116 and HT-29 cells in a dose-dependent manner; downregulated the expression of cycle-related proteins cyclinD1, Rb, and cyclin-dependent kinase 4; induced G2/M phase block; and promoted apoptosis. In addition, Shan et al. [151] found that ursolic acid (UA), the active ingredient contained in Chinese herbs, such as Hedyotic diffusa (Bai Hua She She Cao) and Radix actinidiae (Mi Hou Tao), also exerted anti-proliferative and pro-apoptotic effects on HT-29 cells by a mechanism related to activation of caspase-3 and -9; downregulation of Bcl-2 and Bcl-xL protein expression; and inhibition of phosphorylation of EGFR, RK1/2, p38 MAPK, and JNK expression. This finding suggested that UA may exert anti-CRC effects through inhibition of the EGFR/MAPK signaling pathway (Fig. 5).

p53 signaling pathway

The human p53 gene is located on chromosome 17p, and it consists of 11 exons and 10 introns [152]. As the “guardian of the genome,” p53 could induce cell cycle arrest, apoptosis, or senescence in the presence of cellular stress, thus preventing tumor progression [153]. In normal stress-free cells, the level of p53 remains low. Once p53 is activated, MDM2, an E3 ubiquitin ligase, is upregulated, leading to ubiquitination of p53 and mediation of its degradation, which forms an autoregulatory negative feedback loop [154, 155]. Activation of p53 triggers intrinsic (mitochondria) and extrinsic (death receptors) apoptotic pathways [156]. In the intrinsic pathway, p53 induces the expression of pro-apoptotic Bcl-2 family proteins, such as p53-upregulated modulator of apoptosis and Bax, and downregulates Bcl-2 to trigger permeabilization of the outer mitochondrial membrane. Subsequently, the cytochrome c in the mitochondria is released into the cytoplasm; binds to apoptotic protease activating factor 1; induces activation of promoter caspase-9; and further activates the actuators caspase-3, -6, and -7 [157]. The exogenous pathway mediated by p53 is accompanied by the upregulation of death receptors, such as Fas (CD95/APO-1), DR5 (TRAIL-R2), and p53-induced protein with a death domain, which, together with caspase-8, form a death-inducing signal transduction complex to further activate caspase-3 and induce apoptosis [158]. p53 is the most commonly mutated gene in human cancers [159]. Mutations or loss of function in the p53 gene have been reported in approximately 50–70% of CRC cases [160]. Mutations in p53 not only play a key role in the adenoma-carcinoma transformation of tumors during pathogenesis but also contribute to the aggressiveness of CRC [153, 161]. In addition, p53 interacts with cyclooxygenase-2 to promote inflammation and CRC cell proliferation [162]. Reactivation and restoration of p53 function have great potential in the treatment of CRC (Fig. 6).

Fig. 6
figure 6

The active compounds of TCM act on the p53 signaling pathway. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Icariin is an active ingredient extracted from Herba epimedii (Yin Yang Huo), which has been shown to have antitumor activity against human malignancies [163, 164]. Tian et al. [165] found that the levels of p21, p-p53, and Bax in HCT-116 cells treated with icariin increased, whereas those of Bcl-2 decreased. These results indicated that icariin could induce apoptosis of HCT-116 cells by activating the p53 pathway. Ligustrazine (LZ), the active ingredient in Ligusticum Chuanxiong Hort. (Chuan Xiong), has shown antitumor activity in vitro and in vivo, and it is capable of anti-angiogenesis and reversing drug resistance [166,167,168]. Bian et al. [169] found that LZ could dose-dependently upregulate the levels of p53, Bax, cleaved caspase-3, cleaved caspase-9, and cleaved PARP and downregulate the level of Bcl-2 in SW480 and CT26 cells. Moreover, the expression levels of these proteins were reversed after pretreatment with the p53 inhibitor PFT-α, suggesting that LZ-induced apoptosis of SW480 and CT26 cells was mediated through the p53-dependent mitochondrial pathway. Scutellarin is a flavonoid isolated from Scutellaria barbata D. Don (Ban Zhi Lian). Yang et al. [170] found that the expression of Bcl-2, p-p53, and p21 was significantly decreased, whereas that of Bax was significantly increased in HCT-116 cells after scutellarin intervention. These results suggested that the p53 pathway may be involved in scutellarin-induced apoptosis of HCT-116 cells. In addition, Ganoderma lucidum polysaccharides (GLPs), which are isolated from spores, mycelia, and fruiting bodies of G. lucidum (Ling Zhi), showed anticancer effects [171, 172]. Jiang et al. [173] found that HCT-116 cells transfected with mutant p53R273H and p53248W showed upregulated expression of Bax and p21 and underwent G1 phase cell-cycle arrest and apoptosis after combined treatment of GLPs and GLPs combined with 5-FU. These findings showed that GLPs exert their effects on inducing growth inhibition and apoptosis in CRC cells through reactivation of p53 (Fig. 6).

TGF-β/Smad signaling pathway

The transforming growth factor-β (TGF-β) family proteins include TGF-β1, -β2, and -β3; activins; nodal; bone morphogenetic proteins; and growth proteins and differentiation factors [174]. As a multifunctional cytokine, TGF-β exerts pleiotropic effects on cell physiology, such as proliferation, survival, differentiation, and migration [175]. SMAD proteins are key intracellular signaling mediators and transcription factors for TGF-β superfamily signaling [176]. TGF signaling is initiated by the TGF ligand binding to the type II TGF receptor (TGFBR2). Upon binding to the ligand, TGFBR2 recruits and phosphorylates the type I TGF-β receptor, which, in turn, initiates downstream signaling by phosphorylating the transcription factors SMAD2 and SMAD3 [177] (Fig. 7).

Fig. 7
figure 7

The active compounds of TCM and the Chinese herb formula act on the TGF-β/Smad signaling pathway. JPJD JianPi JieDu Recipe, MSD modified Shenlingbaizhu Decoction, PZH Pien Tze Huang. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

TGF-β plays a double-edged role in the progression of tumors. In normal epithelial cells and early tumor cells, TGF-β increased the expression of CDK inhibitors p15INK4, p21CIP1, p27KIP1, and p57KIP2 via the canonical SMAD pathway to block cell cycle progression [178, 179]. However, in tumor cells, TGF-β promotes tumor progression through mechanisms, such as induction of EMT [180, 181]. The core components of the TGF-β pathway exhibit high levels of loss-of-function mutations in gastrointestinal tumors. In CRC, this phenomenon was mainly manifested by mutations in TGFBR2, SMAD2, and SMAD4, which suppressed the tumor inhibitory ability of TFG-β [182, 183]. In addition, TGF-β receptor could induce other signaling, such as MAPK, PI3K/Akt, Janus kinase-signal transducer, and STAT [184] (Fig. 7).

Celatrol is an effective active ingredient in T. wilfordii Hook F. (Lei Gong Teng), which has anti-inflammatory and anticancer effects [185]. Jiang et al. [186] found that celastrol treatment significantly inhibited the mRNA and protein levels of TGF-β1, TGF-βRI, and TGF-βRII in HCT-116 and SW620 cells. It also inhibited Smad signaling and decreased the expression of p-Smad2/3 and Smad4. These results suggested that the TFG-β/Smad signaling pathway is involved in celastrol-mediated anti-CRC effects. Magnolol is an active ingredient extracted from the bark of Houpu magnolia (Magnolia officinalis) (Hou Pu), and it has a wide range of biological activities [187,188,189]. Chei et al. [190] discovered that in magnolol-treated HCT-116 cells, the expression of epithelial markers, such as E-cadherin, zona occludens 1 (ZO-1), and claudin, increased in a concentration-dependent manner, whereas that of mesenchymal markers, such as N-cadherin, TWIST1, Slug, and Snail, decreased in a concentration-dependent manner. The expression of p-ERK, p-GSK3β, and p-Smad, the downstream proteins of TGF-β signaling pathway, decreased. These results suggested that magnolol inhibits TGF-β-induced EMT by blocking signal transduction downstream of TGF-β signaling. Oxymatrine (OM), the active ingredient in Sophora flavescens Alt. (Ku Shen), could inhibit the growth of various types of tumor cells [191, 192]. Wang et al. [193] found that the expression of E-cadherin was upregulated in RKO cells after OM intervention. On the contrary, the expression of α-smooth muscle actin (α-SMA), fibronectin, TGF-β1, plasminogen activator inhibitor-1 (PAI-1), Smad2/3/4, p-Smad2, and p38 was downregulated, implying that OM could inhibit the TGF-β pathway activation and EMT in CRC by reducing the p38-dependent increase in PAI-1 expression (Fig. 7).

Herbal compounds could also exert anti-CRC effects through the TGF-β/Smad pathway. Liu et al. [194] demonstrated that Jianppi Jieu Recipe (JPJD) could downregulate the expression of p-Smad2/3 and Snail and upregulate the expression of E-cadherin in TGF-β-stimulated Lovo cells in vitro. In-vivo experiments showed that JPJD could upregulate the expression of E-cadherin and downregulate the levels of p-Smad2/3 and Snail in orthotopic CRC tumor tissues in nude mice, suggesting that JPJD may inhibit TGF-β-induced EMT via the expression of Snali/E-cadherin mediated by the TGF-β/Smad2/3 signaling pathway, thus exerting anti-CRC invasive and metastatic effects. Dai et al. [195] found that modified Shenlingbaizhu Decoction (MSD) treatment downregulated the expression of TβRI, CD133, Vimentin, Oct-4 A, and SOX2 in mouse tumor tissues. After the use of TGF-β inhibitor, EMT signal transduction was inhibited, and the pluripotency of colorectal cancer stem cells (CSCs) was reduced. These results suggested that MSD restrains the pluripotency of CSCs by suppressing TGF-β/Smad signaling-induced EMT in vivo while inhibiting the proliferation, migration, and invasion of CRC cells. In addition, Pien Tze Huang could reverse tumor drug resistance by inhibiting the phosphorylation of N-cadherin, TGF-β, Smas2/3, and Smad 4 in tumor tissues while promoting the expression of E-cadherin, thereby inhibiting the movement, invasion, and EMT of CRC cells [196] (Fig. 7).

mTOR signaling pathway

mTOR belongs to the PI3K-related kinase family, a 289 kDa serine/threonine protein kinase containing 2550 amino acids and encoded by 7650 nucleotides [197, 198]. As a major regulator of cell growth and metabolism, mTOR not only promotes the anabolic processes of ribosomes, proteins, nucleotides, fatty acids, and lipids but also inhibits catabolic processes, such as autophagy [199]. In mammals, mTOR contains two major protein complexes with different functions: mTOR complex1 (mTORC1) and mTOR complex2 (mTORC2) [200]. mTORC1 contains mTOR, raptor, mLST8, and two negative regulators, PRAS40 and DEPTOR; it is sensitive to rapamycin [201,202,203,204]. mTORC2 consists of mTOR, rictor, mLST8, mSin1, and the newly identified components Protor, Hsp70, and DEPTOR; it is insensitive to rapamycin treatment [205,206,207,208]. mTOR signaling has been reported to be overactivated in most human cancers, especially in relation to multiple biological processes, such as cell proliferation, survival, autophagy, metabolism, and immunity [199, 209, 210] (Fig. 8).

Fig. 8
figure 8

The active compounds of TCM and the Chinese herb formula act on the mTOR signaling pathway. QFG Qingjie Fuzheng granule, JPJD Jianpi Jiedu Decoction. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

The mTOR signaling pathway may have a direct effect on the carcinogenesis of CRC. Elevated RNA and protein levels of mTORA, raptor, and rictor could be observed in the tissues of patients with CRC, and a correlation was found between the degree of elevated levels of the above expression and the stage of malignancy [211, 212]. Elevated mTORC1 and mTORC2 activities were also associated with EMT and RhoA and Rac1 signaling-mediated CRC metastasis, and it was related to chemoresistance [213]. The anti-CRC effects of currently developed mTOR inhibitors have been demonstrated in in-vivo and -vitro assays [214, 215]. Therefore, targeting the mTOR signaling pathway could benefit CRC treatment (Fig. 8).

Salidroside, the active ingredient in Rhodiola rosea L. (Hong Jing Tian), has been reported to have significant antitumor effects, exerting antiproliferative and pro-apoptotic effects on many types of malignant tumors [216,217,218]. Fan et al. [219] found that LC3-II/LC3-I and Beclin-1 expression were increased and Bcl-2/Bax, p-PI3K, p-AKT, and p-mTOR expressed were decreased in HT-29 cells after salidroside treatment. The above changes were reversed after the use of autophagy inhibitor and PI3K inhibitor. The findings suggested that salidroside may exert its pro-apoptotic and autophagic effects on HT-29 cells by inhibiting the PI3K/Akt/mTOR signaling pathway. Curcumin is the active ingredient of R. Curcumae (Jiang Huang) [220]. Johnson et al. [221] found that curcumin induced Akt phosphorylation in HCT-116 cells while decreasing the expression of mTOR, raptor, and rictor proteins, suggesting that curcumin may exert its anti-proliferative effects on CRC cells through the Akt/mTOR signaling pathway. In addition, andrographolide, the active ingredient in Andrographis paniculata (Chuan Xin Lian), downregulated the expression of PI3K/p110, p-Akt, p-mTOR, and glycolysis-related proteins, such as phosphofructokinase 1, GLUT1, and hexokinase 2, in HCT-116 cells, suggesting that andrographolide may enhance radiosensitivity by inhibiting glycolysis in HCT-116 cells via the PI3K/Akt/mTOR signaling pathway [222]. Nobiletin, an active ingredient in Citrus reticulata Blanco (Gan Ju), has biological effects such as anti-inflammatory, anti-cancer, and neuroprotective effects [223, 224]. Li et al. [225] found that nobiletin could enhance the inhibitory effect of oxaliplatin on the proliferation of HT29 and SW480 cells, while upregulating the expression of pro-apoptotic proteins Bax and caspase3, and downregulating the expression of p-Akt, p-mTOR and anti-apoptotic protein Bcl-2 to promote oxaliplatin-induced apoptosis. The findings above suggested that nobiletin may enhance CRC sensitivity to oxaliplatin by downregulating the PI3K/Akt/mTOR signaling pathway.(Fig. 8).

Zhu et al. [226] found that the Chinese herbal formulation Qingjie Fuzheng granule (QFG) could not only upregulate the expression of E-cadherin, LC3-II, and Beclin-1 but also downregulate the expression of N-cadherin, Vimentin, TWIST1, and p62 in HCT-116 xenograft tumors. Moreover, the ratios of PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR were significantly lower than those in the controls, suggesting that QFG may induce CRC autophagy and thus inhibit EMT progression through the mTOR signaling pathway. Peng et al. [227] found that Jianpi Jiedu Decoction (JPJD) downregulated the expression of mTOR, HIF-1α, VEGF, phosphorylation ribosomal protein S6 kinase (p-p70S6K), and phosphorylation 4E binding protein 1 (p-4E-BP1) in vivo and in vitro, indicating that JPJD regulates the mTOR/HIF-1α/VEGF signaling pathway to exert antitumor activity (Fig. 8).

Hedgehog signaling pathway

In mammals, three ligands of Hedgehog (HH) exist, namely Indian Hedgehog (IHH), Sonic Hedgehog (SHH) and Desert Hedgehog (DHH), capable of participating in the patterning and development of various tissues and organs [228, 229]. Both IHH and SHH can expressed in the gastrointestinal tract, whereas DHH appears to be expressed only in the nervous system and testis [230]. The major components of the HH pathway are located in the cell membrane [231]. The transduction response to HH ligands is mainly regulated and transmitted by two transmembrane proteins: patched (Ptc) and smoothened (Smo), and downstream transcription factors of the Gli family (Gli1, Gli2, and Gli3) [232]. In the absence of its ligand, the HH receptor patched 1 (PTCH1) inhibits Smo function by preventing Smo from entering primary cilia. When HH ligands bind to Ptc, this mutual inhibition is relieved and Smo signaling is activated [233, 234]. The Smo-repressing activity of Ptc is inhibited by binding to HH, thereby releasing Smo and exhibiting its signaling activity within the cell. Smo, located in the primary cilia, signals intracellularly to mediate three Gli zinc finger transcription factors [235]. The transcription factors Gli1, Gli2, and Gli3 are the major downstream executors of HH activation and the key final outputs of HH. Gli1 is an HH-responsive gene product that acts only as a transcriptional activator and participates in a positive feedback loop during pathway activation, while Gli2 and Gli3 act as the main transcriptional activator and transcriptional inhibitor, respectively [236]. Inappropriate activation of the Hedgehog signaling pathway is common in various tumors, such as pancreatic cancer, breast cancer and gastric cancer [237, 238] (Fig. 9).

Fig. 9
figure 9

The active compounds of TCM and the Chinese herb formula act on the Hedgehog signaling pathway. QFG Qingjie Fuzheng granule. The figure was created by Figdraw (https://www.figdraw.com/static/index.html#/)

Numerous studies have shown that the Hedgehog signaling pathway is involved in CRC tumorigenesis. The SHH pathway has a facilitative role in angiogenesis, cell proliferation, and metastasis, while downregulation of IHH has been observed to be an early event in CRC formation [239,240,241]. In addition, the coordination of Smo and Gli, the downstream components of the Hedgehog signaling pathway, plays the most important role in HH regulation of CRC [242]. Cyclopamine, an HH inhibitor, has been demonstrated to anti-proliferation and pro-apoptosis effects in CRC cells [243, 244]. Therefore, regulating the Hedgehog signaling pathway also offers an approach to treating CRC (Fig. 9).

Toosendanin (TSN), an active component derived from MeLia toosendan Sieb. et Zucc. (Chuan Lian Zi), has anti-cancer properties in malignant tumors such pancreatic cancer, gastric cancer, and osteosarcoma [245,246,247,248]. Zhang et al. [249] found that TSN could down-regulate the mRNA and protein levels of SHH, GLI1 and SMO in HT-29 cells in a concentration-dependent manner and inhibit the proliferation of HT-29 cells in vitro. In vivo, it was able to reduce the weight of HT-29 xenograft tumors, meanwhile the protein expression levels of SHH in TSN-treated tumor tissues were significantly lower than those in the control group. These findings implied that TSN may inhibit growth of CRC cells by inhibiting the Hedgehog pathway, and the target of TSN may be SHH. Sun et al. [250] discovered that following Berberine (BBR) treatment, the expression of SHH, Ptch1, SMO, Gli1, and c-Myc was down-regulated while the expression of SUFU was up-regulated in HT-29 cells, suggesting that BBR exerts anti-CRC effects by decreasing the Hedgehog signaling pathway activity. Khan et al. [251] found that andrographolide, the active ingredient in Andrographis paniculata (Chuan Xin Lian), had a strong cytotoxic effect on HCT-116 cells, induced G2/M phase block by downregulating the expression of CDK1 and CyclinB1, downregulated the mRNA levels of Gli1 and SMO, and had a high affinity for the Smo protein. These results indicated that andrographolide may exert anti-CRC effects by suppressing the Hedgehog signaling pathway. Furthermore, Qingjie Fuzheng Granule (QFG) could significantly reduce the protein expression of the Sonic Hedgehog pathway-related proteins SHH, Smo and Gli1 in HCT-116 xenograft mice tumor tissues. It also down-regulated the expression of pro-proliferative survivin Ki-67, CyclinD1, CDK4, VEGF-A and VEGFR-2, and up-regulated the ratio of Bax/Bcl-2 and the expression of p21. These results suggested that QFG exerts anti-CRC effects by inhibiting the Sonic Hedgehog pathway to prevent CRC cells from proliferation, promoting apoptosis and anti-tumor angiogenesis [252] (Fig. 9).

The immunomodulatory signaling pathways

The development of tumors is significantly influenced by the immune system. Tumor incidence rises as the host’s immune system performs worse. The tumor microenvironment (TME), which is strongly associated to tumor invasion and metastasis and encourages tumor progression, is made up of tumor cells, immune cells, extracellular matrix, and interstitial tissue [253]. Cancer immunotherapy is one of the new options for cancer treatment. In contrast to standard treatments such as surgery, radiation and chemotherapy, immunotherapy could effectively overcome the specificity problems associated with radiation and chemotherapy by using and manipulating the patient’s own immune system to fight and destroy tumor cells [254]. Cytokines such as interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and TNF-α play an important role in regulating immune responses and anticancer defense systems [255, 256]. The suppression of immune function and the imbalance of cytokines are the key factors leading to the occurrence and development of cancer and the poor prognosis of patients. Furthermore, immune evasion is one of the hallmarks of tumors. Although natural killer (NK) cells are able to recognize and kill tumor cells, tumor cells from TME are able to inhibit the activity of NK cells [257]. High levels of CD8+ CTL, and CD4+ helper T cells (Th cells) are favorable prognostic factors, while elevated levels of CD4+Tregs indicate a poor prognosis [258]. M1 and M2 are the two main stages of macrophages. T helper (Th-1) cytokines could activate macrophage M1, while Th-2 cytokines such as IL-4 could selectively activate macrophage M2 [259]. Tumor-associated macrophages (TAMs) with the M2 phenotype are important regulators in the occurrence and development of cancer, which can lead to a poor prognosis of cancer patients [260]. Studies have confirmed that immune checkpoint inhibitors (ICIs) can reactivate the immune system and kill tumor cells [261].

TCM has shown potential as ICIs in the treatment of malignant tumors. Unlike Western medicine, which mainly directly kills tumor cells, TCM can systematically regulate TME and exert anti-CRC effects through immunomodulatory signaling pathways [262]. Ganoderma atrum polysaccharide (PSG-1) is a polysaccharide component isolated from the Chinese herb G. lucidum (Ling Zhi) [263]. Zhang et al. [264] found that PSG-1 had no anti-tumor activity in vitro, but was effective in activating peritoneal macrophages in CT26 tumor-bearing mice, enhancing the phagocytic capacity of macrophages and promoting the production of nitric oxide (NO), TNF-α and IL-1β in mice to enhance immune function. Furthermore, it was discovered that PSG-1 acted on toll-like recepetor 4 (TLR4) and then activated NF-κB via the p38 MAPK pathway, promoting TNF-α production, IκBα degradation, and p38 MAPK phosphorylation. The above results suggested that PSG-1 could activate macrophages through TLR4-dependent signaling pathways to enhance immune function and inhibit tumor growth. Panax notoginseng saponins (PNS), the active ingredients extracted from Panax notoginseng (Burk) F.H.Chen (San Qi), have shown anti-tumor effects on CRC cells when used alone or in combination with chemotherapeutic drugs [265, 266]. Li et al. [267] found that PNS had significant preventive and immunomodulatory effects on AOM/DSS-induced CAC mice, and was able to alleviate the immunosuppression of Treg cells in the colonic tissue microenvironment of CAC mice by inhibiting signal transduction and direct mediation of indoleamine 2,3-dioxygenase 1 (IDO1) expression by transcription 1 (STAT1), reducing macrophage aggregation, and reshaping the CAC immune microenvironment. Genkwanin is the active ingredient in Daphne genkwa Sieb. et Zucc. (Yuan Hua). Wang et al. [268] found that genkwanin effectively inhibited the proliferation of HT29 and SW480 cells and the secretion of inflammatory factor IL-8 in vitro, increased the spleen and thymus indices in APCMin/+ mice in vivo, and effectively reduced the levels of IL-1α, IL-1β, IL-8, G-CSF and GM-CSF in mouse colon tissues. These findings suggested that genkwanin has antitumor activity, most likely by enhancing the immune response and decreasing the levels of inflammatory factors.

Conclusion

Intracellular signaling pathways are involved in various biological processes, and they are closely associated with the progression of CRC. TCM has a long history of development and plays an important role in the prevention and treatment of malignant tumors with its unique dialectical concept and holistic concept. In recent years, many basic experiments and clinical studies have confirmed that TCM has a good effect in the treatment of CRC, which can effectively improve the immune function of CRC patients, improve the quality of life, and prolong the survival time [269,270,271]. In this paper, the mechanisms by which TCM exert anti-CRC effects were summarized from the perspective of signaling pathways. TCM could regulate multiple signaling pathways related to CRC progression, including PI3K/Akt, NF-κB, MAPK, Wnt/β-catenin, EGFR, p53, TGF-β, mTOR, Hedgehog, and immunomodulatory signaling pathways, thus affecting biological processes, such as cell proliferation, apoptosis, cell cycle, migration, invasion, autophagy, EMT, angiogenesis, and chemoresistance and ultimately exerting therapeutic effects on CRC (Tables 1 and 2). Given the complexity of CRC pathogenesis, TCM with multiple components, targets, and effects is expected to be a breakthrough in the development of therapeutic CRC drugs. As study on the theory and practice of TCM continues to advance, the avenues and means by which TCM exerts its healing effects could be further elucidated.

Table 1 Effects of TCM and its active ingredients on preventing and treating CRC
Table 2 Effects of Chinese herbal formulas on preventing and treating CRC

In addition, signaling pathways such as Notch [272], is closely associated with CRC progression, and further in-depth studies are needed to prevent and treat CRC through these pathways. The existing reports have only discussed a single signaling pathway and related genes in the progression of CRC, without involving the interaction between signaling pathways. Most of the current studies have revealed the therapeutic effect of TCM on CRC. In vitro cellular models should be combined with in vivo animal models as much as possible, so that the two models can complement each other and jointly promote research on the pathogenesis of CRC and the prevention and treatment of TCM. TCM contains a wealth of resources that should be thoroughly investigated to determine whether other Chinese medical methods such as acupuncture, moxibustion, and acupoint injection have an intervention effect on CRC-related signaling pathways, providing more theoretical support for the use of TCM in malignant tumors. Dialectical analysis of the disease and a grasp of the holistic view of TCM and personalized medicine in the treatment of the disease are lacking. Future studies should pay further attention to the synergistic effect of multiple signaling pathways regulated by TCM on anti-CRC and increase support for the clinical transformation of TCM to provide new ideas and references for the application of TCM in the prevention and treatment of CRC.

Availability of data and materials

No data was used for the research described in the article.

Abbreviations

CRC:

Colorectal cancer

TCM:

Traditional Chinese medicine

IBD:

Inflammatory bowel disease

K-Ras:

Kirsten rat sarcoma

MSI:

Microsatellite-unstable/instability

CDX2:

Caudal-related homeobox 2

MAPK:

Mitogen-activated protein kinase

PI3K:

Phosphatidylinositol 3-kinase

Akt:

Protein kinase-B

RTKs:

Receptor tyrosine kinases

EGFRs:

Epidermal growth factor receptors

EMT:

Epithelial–mesenchymal transition

WOG:

Wogonin

LC3II:

light chain 3-II

Bax:

Bcl-2-associated X

Bcl-2:

B-cell lymphoma-2

p-STAT3:

Phosphorylated signal transducer and activator of transcription 3

EMD:

Emodin

TP:

Triptolide

PD:

Platycodin D

GOD:

Gegen Qinlian Decoction

p-FOXO1:

Phosphorylated forkhead box transcription factor O1

ABTB1:

Ankyrin repeat and BTB/POZ domain containing protein 1

TNSEs:

Tounong powder extracts

p-mTOR:

Phosphorylated mechanistic target of rapamycin

HIF-1α:

Hypoxia-inducible factor-1α

GLUT1:

Glucose transporter type 1

JSD:

Jiedu Sangen decoction

NF-κB:

Nuclear factor kappa-beta

IKK:

IκB kinase

ERK:

Extracellular signal-regulated kinase

ORI:

Oridonin

AP-1:

Activating protein-1

BE:

Baicalein

BBR:

Berberine

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factorα

MMP9:

Matrix metallopeptidase 9

COX2:

Cyclo-oxygenase-2

ICAM-1:

Intercellular adhesion molecule 1

CXCR4:

C-X-C motif chemokine receptor 4

VEGF:

Vascular endothelial growth factor

WMW:

Wu Mei Wan

CAC:

AOM/DSS-induced colitis-associated CRC

IL-6:

Interleukin 6

ZJW:

Zuo Jin Wan

JNK:

Jun N-terminal kinase

MAP2K:

MAPK kinase

MAP3K:

MAPK kinase-kinase

ATF2:

Transcription factor 2

FRA:

Fos-related antigen

Rh1:

Ginsenoside Rh1

PT:

Podophyllotoxin

ROS:

Reactive oxygen species

YQFS:

Yi-Qi-Fu-Sheng

QZC:

Qizhen capsule

NAG-1:

Nonsteroidal anti-inflammatory drug-activated gene-1

GDF15:

Growth differentiation factor-15

AMPK:

AMP-activated protein kinase

GJD:

Geijigajakyak decoction

GSK3β:

Glycogen synthase kinase 3beta

CK1:

Casein kinase 1

APC:

Adenomatous polyposis coli

TCF:

T-cell transcription factor

LEF:

Lymphoid enhancer factor

CTNNB1:

β-catenin

TCF7L2:

Transcription factor-7-like-2

GGC:

Ginkgolide C

WCA:

Weichang’an

ARHGAP25:

Rho GTPase activating protein 25

ZEB1:

Zinc finger E-box binding homeobox 1

5-HTR1D:

5-hydroxytryptamine receptor D

Dvl2:

Dishevelled 2

LEF1:

Lymphoid enhancer-binding factor 1

TCF4:

Transcription factor 4

TK:

Tyrosine kinase

AR:

Am-phiregulin

EGF:

Epidermal growth factor

TGF-α:

Transforming growth factorα

GA:

Gambogic acid

SOX2:

SRY-box transcription factor 2

CD133:

Cluster of differentiation 133

Bmi-1:

B-lymphoma Mo-MLV insertion region 1

ZFP36:

Zinc-finger protein 36

NCTD:

Norcantharidin

UA:

Ursolic acid

LZ:

Ligustrazine

GLPs:

Ganoderma lucidum polysaccharides

TGF-β:

Transforming growth factor-β

TGFBR2:

Type II TGF receptor

ZO-1:

Zona occludens 1

OM:

Oxymatrine

α-SMA:

α-smooth muscle actin

PAI-1:

Plasminogen activator inhibitor-1

CSCs:

Colorectal cancer stem cells

mTORC1:

mTOR complex1

mTORC2:

mTOR complex2

QFG:

Qingjie Fuzheng granule

JPJD:

Jianpi Jiedu Decoction

p-p70S6K:

Phosphorylation ribosomal protein S6 kinase

p-4E-BP1:

Phosphorylation 4E binding protein 1

HH:

Hedgehog

SHH:

Sonic Hedgehog

DHH:

Desert Hedgehog

Ptc:

Patched

Smo:

Smoothened

PTCH1:

patched 1

TSN:

Toosendanin

TME:

Tumor microenvironment

IL-2:

Interleukin-2

IFN-γ:

Interferon-γ

IL-6:

Interleukin-6

NK:

Natural killer

TAMs:

Tumor-associated macrophages

ICIs:

Immune checkpoint inhibitors

PSG-1:

Ganoderma atrum polysaccharide

NO:

Nitric oxide

TLR4:

Toll-like recepetor 4

IDO1:

Indoleamine 2,3-dioxygenase 1

STAT1:

Transcription 1

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.

    Article  PubMed  Google Scholar 

  3. Douaiher J, Ravipati A, Grams B, Chowdhury S, Alatise O, Are C. Colorectal cancer-global burden, trends, and geographical variations. J Surg Oncol. 2017;115(5):619–30.

    Article  PubMed  Google Scholar 

  4. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467–80.

    Article  PubMed  Google Scholar 

  5. Issa IA, Noureddine M. Colorectal cancer screening: an updated review of the available options. World J Gastroenterol. 2017;23(28):5086–96.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yde J, Larsen HM, Laurberg S, Krogh K, Moeller HB. Chronic diarrhoea following surgery for colon cancer-frequency, causes and treatment options. Int J Colorectal Dis. 2018;33(6):683–94.

    Article  PubMed  Google Scholar 

  7. Ni Q, Li M, Yu S. Research progress of epithelial-mesenchymal transition treatment and drug resistance in colorectal cancer. Technol Cancer Res Treat. 2022;21:15330338221081220.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Colussi D, Brandi G, Bazzoli F, Ricciardiello L. Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci. 2013;14(8):16365–85.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sawicki T, Ruszkowska M, Danielewicz A, Niedźwiedzka E, Arłukowicz T, Przybyłowicz KE. A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers. 2021;13(9):2025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Le Marchand L, Wilkens LR, Hankin JH, Kolonel LN, Lyu LC. A case-control study of diet and colorectal cancer in a multiethnic population in Hawaii (United States): lipids and foods of animal origin. Cancer Causes Control. 1997;8(4):637–48.

    Article  PubMed  Google Scholar 

  11. Cross AJ, Ferrucci LM, Risch A, Graubard BI, Ward MH, Park Y, et al. A large prospective study of meat consumption and colorectal cancer risk: an investigation of potential mechanisms underlying this association. Cancer Res. 2010;70(6):2406–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Munro MJ, Wickremesekera SK, Peng L, Tan ST, Itinteang T. Cancer stem cells in colorectal cancer: a review. J Clin Pathol. 2018;71(2):110–6.

    Article  CAS  PubMed  Google Scholar 

  13. Chen K, Collins G, Wang H, Toh JWT. Pathological features and prognostication in colorectal cancer. Curr Oncol. 2021;28(6):5356–83.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sclafani F, Gullo G, Sheahan K, Crown J. BRAF mutations in melanoma and colorectal cancer: a single oncogenic mutation with different tumour phenotypes and clinical implications. Crit Rev Oncol Hematol. 2013;87(1):55–68.

    Article  CAS  PubMed  Google Scholar 

  15. French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res. 2008;14(11):3408–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liou JM, Wu MS, Shun CT, Chiu HM, Chen MJ, Chen CC, et al. Mutations in BRAF correlate with poor survival of colorectal cancers in Chinese population. Int J Colorectal Dis. 2011;26(11):1387–95.

    Article  PubMed  Google Scholar 

  17. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–32.

    Article  CAS  PubMed  Google Scholar 

  18. Taieb J, Le Malicot K, Shi Q, Penault-Llorca F, Bouché O, Tabernero J, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2016;109(5):djw272.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Andersen SN, Løvig T, Breivik J, Lund E, Gaudernack G, Meling GI, et al. K-ras mutations and prognosis in large-bowel carcinomas. Scand J Gastroenterol. 1997;32(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  20. Cefalì M, Epistolio S, Palmarocchi MC, Frattini M, De Dosso S. Research progress on KRAS mutations in colorectal cancer. J Cancer Metastasis Treat. 2021;7:26.

    Google Scholar 

  21. Verzi MP, Shin H, Ho LL, Liu XS, Shivdasani RA. Essential and redundant functions of caudal family proteins in activating adult intestinal genes. Mol Cell Biol. 2011;31(10):2026–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bonhomme C, Duluc I, Martin E, Chawengsaksophak K, Chenard MP, Kedinger M, et al. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Gut. 2003;52(10):1465–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hryniuk A, Grainger S, Savory JG, Lohnes D. Cdx1 and Cdx2 function as tumor suppressors. J Biol Chem. 2014;289(48):33343–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. El-Shami K, Oeffinger KC, Erb NL, Willis A, Bretsch JK, Pratt-Chapman ML, et al.American Cancer Society colorectal cancer survivorship care guidelines. CA Cancer J Clin. 2015;65(6):428–55.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Pachman DR, Qin R, Seisler DK, Smith EM, Beutler AS, Ta LE, et al. Clinical course of oxaliplatin-induced neuropathy: results from the randomized phase III trial N08CB (Alliance). J Clin Oncol. 2015;33(30):3416–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kong MY, Li LY, Lou YM, Chi HY, Wu JJ. Chinese herbal medicines for prevention and treatment of colorectal cancer: from molecular mechanisms to potential clinical applications. J Integr Med. 2020;18(5):369–84.

    Article  PubMed  Google Scholar 

  27. Paul S, Roy D, Pati S, Sa G. The adroitness of andrographolide as a natural weapon against colorectal cancer. Front Pharmacol. 2021;12:731492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ranjan A, Ramachandran S, Gupta N, Kaushik I, Wright S, Srivastava S, et al. Role of phytochemicals in cancer prevention. Int J Mol Sci. 2019;20(20):4981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maeda Y, Takahashi H, Nakai N, Yanagita T, Ando N, Okubo T, et al. Apigenin induces apoptosis by suppressing bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer. Int J Oncol. 2018;52(5):1661–73.

    CAS  PubMed  Google Scholar 

  30. Yao S, Wang X, Li C, Zhao T, Jin H, Fang W. Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway. Tumour Biol. 2016;37(8):10247–56.

    Article  CAS  PubMed  Google Scholar 

  31. Deng S, Hu B, An HM, Du Q, Xu L, Shen KP, et al. Teng-Long-Bu-Zhong-Tang, a Chinese herbal formula, enhances anticancer effects of 5–Fluorouracil in CT26 colon carcinoma. BMC Complement Altern Med. 2013;13:128.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hu B, An HM, Wang SS, Zheng JL, Yan X, Huang XW, et al. Teng-Long-Bu-Zhong-Tang induces p21-dependent cell senescence in colorectal carcinoma LS174T cells via histone acetylation. J Exp Pharmacol. 2017;9:67–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Khezri MR, Jafari R, Yousefi K, Zolbanin NM. The PI3K/AKT signaling pathway in cancer: molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol. 2022;127:104787.

    Article  CAS  PubMed  Google Scholar 

  35. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard akt to follow. Trends Biochem Sci. 2001;26(11):657–64.

    Article  CAS  PubMed  Google Scholar 

  37. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.

    Article  CAS  PubMed  Google Scholar 

  38. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16(1):21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fortier AM, Asselin E, Cadrin M. Functional specificity of akt isoforms in cancer progression. Biomol Concepts. 2011;2(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  40. Jiang N, Dai Q, Su X, Fu J, Feng X, Peng J. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep. 2020;47(6):4587–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou Y, Li S, Li J, Wang D, Li Q. Effect of microRNA-135a on cell proliferation, migration, invasion, apoptosis and tumor angiogenesis through the IGF-1/PI3K/Akt signaling pathway in non-small cell lung cancer. Cell Physiol Biochem. 2017;42(4):1431–46.

    Article  CAS  PubMed  Google Scholar 

  42. Ma Z, Otsuyama K, Liu S, Abroun S, Ishikawa H, Tsuyama N, et al. Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells. Blood. 2005;105(8):3312–8.

    Article  CAS  PubMed  Google Scholar 

  43. Kyo R, Nakahata N, Sakakibara I, Kubo M, Ohizumi Y. Baicalin and baicalein, constituents of an important medicinal plant, inhibit intracellular Ca2 + elevation by reducing phospholipase C activity in C6 rat glioma cells. J Pharm Pharmacol. 1998;50(10):1179–82.

    Article  CAS  PubMed  Google Scholar 

  44. Tan H, Li X, Yang WH, Kang Y. A flavone, wogonin from Scutellaria baicalensis inhibits the proliferation of human colorectal cancer cells by inducing of autophagy, apoptosis and G2/M cell cycle arrest via modulating the PI3K/AKT and STAT3 signalling pathways. J BUON. 2019;24(3):1143–9.

    PubMed  Google Scholar 

  45. Wen X, Zhang X, Qu S, Chen X, Liu C, Yang Y. Coptisine induces G2/M arrest in esophageal cancer cell via the inhibition of p38/ERK1/2/claudin-2 signaling pathway. Pharmazie. 2021;76(5):202–7.

    CAS  PubMed  Google Scholar 

  46. Kim SY, Hwangbo H, Kim MY, Ji SY, Lee H, Kim GY, et al. Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Arch Biochem Biophys. 2021;697:108688.

    Article  CAS  PubMed  Google Scholar 

  47. Huang T, Xiao Y, Yi L, Li L, Wang M, Tian C, et al. Coptisine from Rhizoma Coptidis suppresses HCT-116 cells-related tumor growth in vitro and in vivo. Sci Rep. 2017;7:38524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dong X, Fu J, Yin X, Cao S, Li X, Lin L, et al. Emodin: a review of its pharmacology, toxicity and pharmacokinetics. Phytother Res. 2016;30(8):1207–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dai G, Ding K, Cao Q, Xu T, He F, Liu S, et al. Emodin suppresses growth and invasion of colorectal cancer cells by inhibiting VEGFR2. Eur J Pharmacol. 2019;859:172525.

    Article  CAS  PubMed  Google Scholar 

  50. Liu J, Shen M, Yue Z, Yang Z, Wang M, Li C, et al. Triptolide inhibits colon-rectal cancer cells proliferation by induction of G1 phase arrest through upregulation of p21. Phytomedicine. 2012;19(8–9):756–62.

    Article  CAS  PubMed  Google Scholar 

  51. Xie Y, Deng W, Sun H, Li D. Platycodin D2 is a potential less hemolytic saponin adjuvant eliciting Th1 and Th2 immune responses. Int Immunopharmacol. 2008;8(8):1143–50.

    Article  CAS  PubMed  Google Scholar 

  52. Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS. Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum saponins via suppression of nuclear factor-kappab activation in RAW 264.7 cells. Life Sci. 2005;76(20):2315–28.

    Article  CAS  PubMed  Google Scholar 

  53. Lee H, Kang R, Kim YS, Chung SI, Yoon Y. Platycodin D inhibits adipogenesis of 3T3-L1 cells by modulating Kruppel-like factor 2 and peroxisome proliferator-activated receptor gamma. Phytother Res. 2010;24(Suppl 2):161–7.

    Article  Google Scholar 

  54. Liu Y, Tian S, Yi B, Feng Z, Chu T, Liu J, et al. Platycodin D sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway. Front Oncol. 2022;12:1046143.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Li F, Chen L, Zheng J, Yang J, Song X, Wang Y, et al. Mechanism of Gegen Qinlian Decoction regulating ABTB1 expression in colorectal cancer metastasis based on PI3K/AKT/FOXO1 pathway. Biomed Res Int. 2022;2022:8131531.

    PubMed  PubMed Central  Google Scholar 

  56. Fang LH, Liu SL, Wang RP, Hu SY, Ju WZ, Li CY. Tounong Powder (透脓散) extracts induce G1 cell cycle arrest and apoptosis in LoVo cells. Chin J Integr Med. 2016. https://doi.org/10.1007/s11655-016-2597-8.

    Article  PubMed  Google Scholar 

  57. Sun LT, Zhang LY, Shan FY, Shen MH, Ruan SM. Jiedu Sangen decoction inhibits chemoresistance to 5-fluorouracil of colorectal cancer cells by suppressing glycolysis via PI3K/AKT/HIF-1α signaling pathway. Chin J Nat Med. 2021;19(2):143–52.

    CAS  PubMed  Google Scholar 

  58. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–79.

    Article  CAS  PubMed  Google Scholar 

  59. Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–83.

    Article  CAS  PubMed  Google Scholar 

  60. Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001;107(3):241–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Giridharan S, Srinivasan M. Mechanisms of NF-κB p65 and strategies for therapeutic manipulation. J Inflamm Res. 2018;11:407–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25(6):280–8.

    Article  CAS  PubMed  Google Scholar 

  63. Soleimani A, Rahmani F, Ferns GA, Ryzhikov M, Avan A, Hassanian SM. Role of the NF-κB signaling pathway in the pathogenesis of colorectal cancer. Gene. 2020;726:144132.

    Article  CAS  PubMed  Google Scholar 

  64. Hassanzadeh P. Colorectal cancer and NF-κB signaling pathway. Gastroenterol Hepatol Bed Bench. 2011;4(3):127–32.

    PubMed  PubMed Central  Google Scholar 

  65. Sakamoto K, Maeda S. Targeting NF-kappaB for colorectal cancer. Expert Opin Ther Targets. 2010;14(6):593–601.

    Article  CAS  PubMed  Google Scholar 

  66. Evertsson S, Sun XF. Protein expression of NF-kappaB in human colorectal adenocarcinoma. Int J Mol Med. 2002;10(5):547–50.

    CAS  PubMed  Google Scholar 

  67. Lin G, Tang Z, Ye YB, Chen Q. NF-κB activity is downregulated by KRAS knockdown in SW620 cells via the RAS-ERK-IκBα pathway. Oncol Rep. 2012;27(5):1527–34.

    CAS  PubMed  Google Scholar 

  68. Li CY, Wang EQ, Cheng Y, Bao JK. Oridonin: an active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. Int J Biochem Cell Biol. 2011;43(5):701–4.

    Article  CAS  PubMed  Google Scholar 

  69. Chen S, Gao J, Halicka HD, Huang X, Traganos F, Darzynkiewicz Z. The cytostatic and cytotoxic effects of oridonin (rubescenin), a diterpenoid from Rabdosia rubescens, on tumor cells of different lineage. Int J Oncol. 2005;26(3):579–88.

    PubMed  Google Scholar 

  70. Ikezoe T, Chen SS, Tong XJ, Heber D, Taguchi H, Koeffler HP. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol. 2003;23(4):1187–93.

    CAS  PubMed  Google Scholar 

  71. Jin H, Tan X, Liu X, Ding Y. Downregulation of AP-1 gene expression is an initial event in the oridonin-mediated inhibition of colorectal cancer: studies in vitro and in vivo. J Gastroenterol Hepatol. 2011;26(4):706–15.

    Article  CAS  PubMed  Google Scholar 

  72. Li-Weber M. New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev. 2009;35(1):57–68.

    Article  CAS  PubMed  Google Scholar 

  73. Kim DH, Hossain MA, Kang YJ, Jang JY, Lee YJ, Im E, et al. Baicalein, an active component of Scutellaria baicalensis Georgi, induces apoptosis in human colon cancer cells and prevents AOM/DSS-induced colon cancer in mice. Int J Oncol. 2013;43(5):1652–8.

    Article  CAS  PubMed  Google Scholar 

  74. Chen H, Ye C, Cai B, Zhang F, Wang X, Zhang J, et al. Berberine inhibits intestinal carcinogenesis by suppressing intestinal pro-inflammatory genes and oncogenic factors through modulating gut microbiota. BMC Cancer. 2022;22(1):566.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kunnumakkara AB, Diagaradjane P, Anand P, Harikumar KB, Deorukhkar A, Gelovani J, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int J Cancer. 2009;125(9):2187–97.

    Article  CAS  PubMed  Google Scholar 

  76. Li XM. Complementary and alternative medicine for treatment of food allergy. Immunol Allergy Clin North Am. 2018;38(1):103–24.

    Article  CAS  PubMed  Google Scholar 

  77. Jiang F, Liu M, Wang H, Shi G, Chen B, Chen T, et al. Wu Mei Wan attenuates CAC by regulating gut microbiota and the NF-kB/IL6-STAT3 signaling pathway. Biomed Pharmacother. 2020;125:109982.

    Article  CAS  PubMed  Google Scholar 

  78. Sui H, Pan SF, Feng Y, Jin BH, Liu X, Zhou LH, et al. Zuo Jin Wan reverses P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway. BMC Complement Altern Med. 2014;14:279.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.

    Article  CAS  PubMed  Google Scholar 

  80. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802(4):396–405.

    Article  CAS  PubMed  Google Scholar 

  81. Krens SF, Spaink HP, Snaar-Jagalska BE. Functions of the MAPK family in vertebrate-development. FEBS Lett. 2006;580(21):4984–90.

    Article  CAS  PubMed  Google Scholar 

  82. Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120(22):3446–56.

    Article  CAS  PubMed  Google Scholar 

  83. Salles D, Santino SF, Ribeiro DA, Malinverni ACM, Stávale JN. The involvement of the MAPK pathway in pilocytic astrocytomas. Pathol Res Pract. 2022;232:153821.

    Article  CAS  PubMed  Google Scholar 

  84. Morrison DK, Davis RJ. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003;19:91–118.

    Article  CAS  PubMed  Google Scholar 

  85. Kciuk M, Gielecińska A, Budzinska A, Mojzych M, Kontek R. Metastasis and MAPK pathways. Int J Mol Sci. 2022;23(7):3847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A Comprehensive Review on MAPK: a promising therapeutic target in Cancer. Cancers (Basel). 2019;11(10):1618.

    Article  CAS  PubMed  Google Scholar 

  87. Gao J, Wang Y, Yang J, Zhang W, Meng K, Sun Y, et al. RNF128 promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 pathway in esophageal squamous cell carcinoma. Cancers (Basel). 2019;11(6):840.

    Article  CAS  PubMed  Google Scholar 

  88. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103(2):239–52.

    Article  CAS  PubMed  Google Scholar 

  89. Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9(8):537–49.

    Article  CAS  PubMed  Google Scholar 

  90. Li YS, Deng ZH, Zeng C, Lei GH. JNK pathway in osteosarcoma: pathogenesis and therapeutics. J Recept Signal Transduct Res. 2016;36(5):465–70.

    Article  PubMed  Google Scholar 

  91. Yoon JH, Choi YJ, Lee SG. Ginsenoside Rh1 suppresses matrix metalloproteinase-1 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathway in human hepatocellular carcinoma cells. Eur J Pharmacol. 2012;679(1–3):24–33.

    CAS  PubMed  Google Scholar 

  92. Choi YJ, Yoon JH, Cha SW, Lee SG. Ginsenoside Rh1 inhibits the invasion and migration of THP-1 acute monocytic leukemia cells via inactivation of the MAPK signaling pathway. Fitoterapia. 2011;82(6):911–9.

    Article  CAS  PubMed  Google Scholar 

  93. Jung JS, Ahn JH, Le TK, Kim DH, Kim HS. Protopanaxatriol ginsenoside Rh1 inhibits the expression of matrix metalloproteinases and the in vitro invasion/migration of human astroglioma cells. Neurochem Int. 2013;63(2):80–6.

    Article  CAS  PubMed  Google Scholar 

  94. Lyu X, Xu X, Song A, Guo J, Zhang Y, Zhang Y. Ginsenoside Rh1 inhibits colorectal cancer cell migration and invasion in vitro and tumor growth in vivo. Oncol Lett. 2019;18(4):4160–6.

    PubMed  PubMed Central  Google Scholar 

  95. Ma ZJ, Meng ZK, Zhang P. Chemical constituents from the radix of Curcuma wenyujin. Fitoterapia. 2009;80(6):374–6.

    Article  CAS  PubMed  Google Scholar 

  96. Shen Y, Lu B, Zhang S, Ma ZJ. Diterpenoid C of Radix Curcumae: an inhibitor of proliferation and inducer of apoptosis in human colon adenocarcinoma cells acting via inhibiting MAPK signaling pathway. Pharm Biol. 2014;52(9):1158–65.

    Article  CAS  PubMed  Google Scholar 

  97. Canel C, Moraes RM, Dayan FE, Ferreira D. Podophyllotoxin. Phytochemistry. 2000;54(2):115–20.

    Article  CAS  PubMed  Google Scholar 

  98. Shah Z, Gohar UF, Jamshed I, Mushtaq A, Mukhtar H, Zia-Ui-Haq M, et al. Podophyllotoxin: history, recent advances and future prospects. Biomolecules. 2021;11(4):603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zi CT, Yang L, Kong QH, Li HM, Yang XZ, Ding ZT, et al. Glucoside derivatives of podophyllotoxin: synthesis, physicochemical properties, and cytotoxicity. Drug Des Devel Ther. 2019;13:3683–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lee SO, Joo SH, Kwak AW, Lee MH, Seo JH, Cho SS, et al. Podophyllotoxin induces ROS-Mediated apoptosis and cell cycle arrest in human colorectal cancer cells via p38 MAPK signaling. Biomol Ther. 2021;29(6):658–66.

    Article  Google Scholar 

  101. Deng W, Sui H, Wang Q, He N, Duan C, Han L, et al. A Chinese herbal formula, Yi-Qi-Fu-Sheng, inhibits migration/invasion of colorectal cancer by down-regulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways. BMC Complement Altern Med. 2013;13:65.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Guo D, Guo C, Fang L, Sang T, Wang Y, Wu K, et al. Qizhen capsule inhibits colorectal cancer by inducing NAG-1/GDF15 expression that mediated via MAPK/ERK activation. J Ethnopharmacol. 2021;273:113964.

    Article  CAS  PubMed  Google Scholar 

  103. Lee SI, Bae JA, Ko YS, Lee KI, Kim H, Kim KK. Geijigajakyak decoction inhibits the motility and tumorigenesis of colorectal cancer cells. BMC Complement Altern Med. 2016;16(1):288.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Bian J, Dannappel M, Wan C, Firestein R. Transcriptional regulation of Wnt/β-Catenin pathway in colorectal cancer. Cells. 2020;9(9):2125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Amin N, Vincan E. The wnt signaling pathways and cell adhesion. Front Biosci (Landmark Ed). 2012;17(2):784–804.

    Article  CAS  PubMed  Google Scholar 

  106. Gajos-Michniewicz A, Czyz M. WNT signaling in melanoma. Int J Mol Sci. 2020;21(14):4852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Disoma C, Zhou Y, Li S, Peng J, Xia Z. Wnt/β-catenin signaling in colorectal cancer: is therapeutic targeting even possible? Biochimie. 2022;195:39–53.

    Article  CAS  PubMed  Google Scholar 

  108. Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev. 2006;20(11):1394–404.

    Article  CAS  PubMed  Google Scholar 

  109. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Byun WS, Bae ES, Kim WK, Lee SK. Antitumor activity of rutaecarpine in human colorectal cancer cells by suppression of Wnt/β-catenin signaling. J Nat Prod. 2022;85(5):1407–18.

    Article  CAS  PubMed  Google Scholar 

  111. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(1):3.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Nusse R, Clevers H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99.

    Article  CAS  PubMed  Google Scholar 

  113. Hadjihannas MV, Bernkopf DB, Brückner M, Behrens J. Cell cycle control of Wnt/β-catenin signalling by conductin/axin2 through CDC20. EMBO Rep. 2012;13(4):347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Qi J, Yu Y, Akilli Öztürk Ö, Holland JD, Besser D, Fritzmann J, et al. New Wnt/β-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals. Gut. 2016;65(10):1690–701.

    Article  CAS  PubMed  Google Scholar 

  115. Damodharan U, Ganesan R, Radhakrishnan UC. Expression of MMP2 and MMP9 (gelatinases A and B) in human colon cancer cells. Appl Biochem Biotechnol. 2011;165(5–6):1245–52.

    Article  CAS  PubMed  Google Scholar 

  116. Suboj P, Babykutty S, Srinivas P, Gopala S. Aloe emodin induces G2/M cell cycle arrest and apoptosis via activation of caspase-6 in human colon cancer cells. Pharmacology. 2012;89(1–2):91–8.

    Article  CAS  PubMed  Google Scholar 

  117. Pooja T, Karunagaran D. Emodin suppresses wnt signaling in human colorectal cancer cells SW480 and SW620. Eur J Pharmacol. 2014;742:55–64.

    Article  CAS  PubMed  Google Scholar 

  118. Zeng Z, Zhu J, Chen L, Wen W, Yu R. Biosynthesis pathways of ginkgolides. Pharmacogn Rev. 2013;7(13):47–52.

    PubMed  PubMed Central  Google Scholar 

  119. van Beek TA, Montoro P. Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 2009;1216(11):2002–32.

    Article  PubMed  Google Scholar 

  120. Yang MH, Ha IJ, Lee SG, Lee J, Um JY, Ahn KS. Ginkgolide C promotes apoptosis and abrogates metastasis of colorectal carcinoma cells by targeting Wnt/β-catenin signaling pathway. IUBMB Life. 2021;73(10):1222–34.

    Article  CAS  PubMed  Google Scholar 

  121. Wang Y, Yu J, Cui R, Lin J, Ding X. Curcumin in treating breast cancer: a review. J Lab Autom. 2016;21(6):723–31.

    Article  CAS  PubMed  Google Scholar 

  122. Zhou S, Yao D, Guo L, Teng L. Curcumin suppresses gastric cancer by inhibiting gastrin-mediated acid secretion. FEBS Open Bio. 2017;7(8):1078–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mehta HJ, Patel V, Sadikot RT. Curcumin and lung cancer—a review. Target Oncol. 2014;9(4):295–310.

    Article  PubMed  Google Scholar 

  124. Jiang X, Li S, Qiu X, Cong J, Zhou J, Miu W. Curcumin inhibits cell viability and increases apoptosis of SW620 human colon adenocarcinoma cells via the caudal type homeobox-2 (CDX2)/Wnt/β-catenin pathway. Med Sci Monit. 2019;25:7451–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jugait S, Areti A, Nellaiappan K, Narwani P, Saha P, Velayutham R, et al. Neuroprotective effect of baicalein against oxaliplatin-Induced peripheral neuropathy: impact on oxidative stress, neuro-inflammation and WNT/β-catenin signaling. Mol Neurobiol. 2022;59(7):4334–50.

    Article  CAS  PubMed  Google Scholar 

  126. Tao L, Gu Y, Zheng J, Yang J, Zhu Y. Weichang’an suppressed migration and invasion of HCT116 cells by inhibiting Wnt/β-catenin pathway while upregulating ARHGAP25. Biotechnol Appl Biochem. 2019;66(5):787–93.

    Article  CAS  PubMed  Google Scholar 

  127. Pan J, Xu Y, Song H, Zhou X, Yao Z, Ji G. Extracts of Zuo Jin Wan, a traditional Chinese medicine, phenocopies 5-HTR1D antagonist in attenuating Wnt/β-catenin signaling in colorectal cancer cells. BMC Complement Altern Med. 2017;17(1):506.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Zhang MM, Yin DK, Rui XL, Shao FP, Li JC, Xu L, et al. Protective effect of Pai-Nong-San against AOM/DSS-induced CAC in mice through inhibiting the wnt signaling pathway. Chin J Nat Med. 2021;19(12):912–20.

    CAS  PubMed  Google Scholar 

  129. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12(18):5268–72.

    Article  CAS  PubMed  Google Scholar 

  130. Schlessinger J, Lemmon MA. Nuclear signaling by receptor tyrosine kinases: the first robin of spring. Cell. 2006;127(1):45–8.

    Article  CAS  PubMed  Google Scholar 

  131. Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33(4):369–85.

    Article  CAS  PubMed  Google Scholar 

  132. Klein S, Levitzki A. Targeting the EGFR and the PKB pathway in cancer. Curr Opin Cell Biol. 2009;21(2):185–93.

    Article  CAS  PubMed  Google Scholar 

  133. Schlessinger J. Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb Perspect Biol. 2014;6(3):a008912.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Press MF, Lenz HJ. EGFR, HER2 and VEGF pathways: validated targets for cancer treatment. Drugs. 2007;67(14):2045–75.

    Article  CAS  PubMed  Google Scholar 

  135. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19(3):183–232.

    Article  CAS  PubMed  Google Scholar 

  136. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.

    Article  CAS  PubMed  Google Scholar 

  138. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(Suppl 1):24–31.

    Article  Google Scholar 

  139. Herbst RS, Langer CJ. Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin Oncol. 2002;29(1 Suppl 4):27–36.

    Article  CAS  PubMed  Google Scholar 

  140. Polychronis A, Sinnett HD, Hadjiminas D, Singhal H, Mansi JL, Shivapatham D, et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol. 2005;6(6):383–91.

    Article  CAS  PubMed  Google Scholar 

  141. Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7):692–700.

    Article  PubMed  Google Scholar 

  142. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705.

    Article  CAS  PubMed  Google Scholar 

  143. Ali BH, Blunden G, Tanira MO, Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food Chem Toxicol. 2008;46(2):409–20.

    Article  CAS  PubMed  Google Scholar 

  144. Hu SM, Yao XH, Hao YH, Pan AH, Zhou XW. 8Gingerol regulates colorectal cancer cell proliferation and migration through the EGFR/STAT/ERK pathway. Int J Oncol. 2020;56(1):390–7.

    CAS  PubMed  Google Scholar 

  145. Guo QL, Lin SS, You QD, Gu HY, Yu J, Zhao L, et al. Inhibition of human telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma SMMC-7721 cells. Life Sci. 2006;78(11):1238–45.

    Article  CAS  PubMed  Google Scholar 

  146. Zhao L, Guo QL, You QD, Wu ZQ, Gu HY. Gambogic acid induces apoptosis and regulates expressions of bax and Bcl-2 protein in human gastric carcinoma MGC-803 cells. Biol Pharm Bull. 2004;27(7):998–1003.

    Article  CAS  PubMed  Google Scholar 

  147. Wu ZQ, Guo QL, You QD, Zhao L, Gu HY. Gambogic acid inhibits proliferation of human lung carcinoma SPC-A1 cells in vivo and in vitro and represses telomerase activity and telomerase reverse transcriptase mRNA expression in the cells. Biol Pharm Bull. 2004;27(11):1769–74.

    Article  CAS  PubMed  Google Scholar 

  148. Wei F, Zhang T, Yang Z, Wei JC, Shen HF, Xiao D, et al. Gambogic acid efficiently kills stem-like colorectal cancer cells by upregulating ZFP36 expression. Cell Physiol Biochem. 2018;46(2):829–46.

    Article  CAS  PubMed  Google Scholar 

  149. Hsieh CH, Chao KS, Liao HF, Chen YJ. Norcantharidin, derivative of cantharidin, for cancer stem cells. Evid Based Complement Alternat Med. 2013;2013:838651.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Qiu P, Wang S, Liu M, Ma H, Zeng X, Zhang M, et al. Norcantharidin inhibits cell growth by suppressing the expression and phosphorylation of both EGFR and c-Met in human colon cancer cells. BMC Cancer. 2017;17(1):55.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Shan JZ, Xuan YY, Zheng S, Dong Q, Zhang SZ. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J Zhejiang Univ Sci B. 2009;10(9):668–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Saha MN, Qiu L, Chang H. Targeting p53 by small molecules in hematological malignancies. J Hematol Oncol. 2013;6:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Li XL, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015;21(1):84–93.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin Cancer Res. 2011;17(9):2830–41.

    Article  CAS  PubMed  Google Scholar 

  155. Li Q, Lozano G. Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy. Clin Cancer Res. 2013;19(1):34–41.

    Article  PubMed  Google Scholar 

  156. Ryan KM, Phillips AC, Vousden KH. Regulation and function of the p53 tumor suppressor protein. Curr Opin Cell Biol. 2001;13(3):332–7.

    Article  CAS  PubMed  Google Scholar 

  157. Read SH, Baliga BC, Ekert PG, Vaux DL, Kumar S. A novel apaf-1-independent putative caspase-2 activation complex. J Cell Biol. 2002;159(5):739–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Shen J, Vakifahmetoglu H, Stridh H, Zhivotovsky B, Wiman KG. PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene. 2008;27(51):6571–80.

    Article  CAS  PubMed  Google Scholar 

  159. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Smith G, Carey FA, Beattie J, Wilkie MJ, Lightfoot TJ, Coxhead J, et al. Mutations in APC, Kirsten-ras, and p53–alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA. 2002;99(14):9433–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. López I, Oliveira P, Tucci L, Alvarez-Valín P, Coudry FA, Marín R. Different mutation profiles associated to P53 accumulation in colorectal cancer. Gene. 2012;499(1):81–7.

    Article  PubMed  Google Scholar 

  162. Malki A, ElRuz RA, Gupta I, Allouch A, Vranic S, Al Moustafa AE. Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements. Int J Mol Sci. 2020;22(1):130.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Wang Y, Dong H, Zhu M, Ou Y, Zhang J, Luo H, et al. Icariin exterts negative effects on human gastric cancer cell invasion and migration by vasodilator-stimulated phosphoprotein via Rac1 pathway. Eur J Pharmacol. 2010;635(1–3):40–8.

    Article  CAS  PubMed  Google Scholar 

  164. Song L, Chen X, Mi L, Liu C, Zhu S, Yang T, et al. Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer. Cancer Sci. 2020;111(11):4242–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tian M, Yang S, Yan X. Icariin reduces human colon carcinoma cell growth and metastasis by enhancing p53 activities. Braz J Med Biol Res. 2018;51(10):e7151.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Pan J, Shang JF, Jiang GQ, Yang ZX. Ligustrazine induces apoptosis of breast cancer cells in vitro and in vivo. J Cancer Res Ther. 2015;11(2):454–8.

    Article  CAS  PubMed  Google Scholar 

  167. Cheng L, Ma H, Shao M, Fan Q, Lv H, Peng J, et al. Synthesis of folatechitosan nanoparticles loaded with ligustrazine to target folate receptor positive cancer cells. Mol Med Rep. 2017;16(2):1101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen L, Lu Y, Wu JM, Xu B, Zhang LJ, Gao M, et al. Ligustrazine inhibits B16F10 melanoma metastasis and suppresses angiogenesis induced by vascular endothelial growth factor. Biochem Biophys Res Commun. 2009;386(2):374–9.

    Article  CAS  PubMed  Google Scholar 

  169. Bian Y, Yang L, Sheng W, Li Z, Xu Y, Li W, et al. Ligustrazine induces the colorectal cancer cells apoptosis via p53-dependent mitochondrial pathway and cell cycle arrest at the G0/G1 phase. Ann Palliat Med. 2021;10(2):1578–88.

    Article  PubMed  Google Scholar 

  170. Yang N, Zhao Y, Wang Z, Liu Y, Zhang Y. Scutellarin suppresses growth and causes apoptosis of human colorectal cancer cells by regulating the p53 pathway. Mol Med Rep. 2017;15(2):929–35.

    Article  CAS  PubMed  Google Scholar 

  171. Xu Z, Chen X, Zhong Z, Chen L, Wang Y. Ganoderma lucidum polysaccharides: immunomodulation and potential anti-tumor activities. Am J Chin Med. 2011;39(1):15–27.

    Article  PubMed  Google Scholar 

  172. Shang D, Li Y, Wang C, Wang X, Yu Z, Fu X. A novel polysaccharide from Se-enriched Ganoderma lucidum induces apoptosis of human breast cancer cells. Oncol Rep. 2011;25(1):267–72.

    CAS  PubMed  Google Scholar 

  173. Jiang D, Wang L, Zhao T, Zhang Z, Zhang R, Jin J, et al. Restoration of the tumor-suppressor function to mutant p53 by Ganoderma lucidum polysaccharides in colorectal cancer cells. Oncol Rep. 2017;37(1):594–600.

    Article  CAS  PubMed  Google Scholar 

  174. Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 2016;8(5):a021873.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103(2):295–309.

    Article  PubMed  Google Scholar 

  176. Yu Y, Feng XH. TGF-β signaling in cell fate control and cancer. Curr Opin Cell Biol. 2019;61:56–63.

    Article  CAS  PubMed  Google Scholar 

  177. Bellam N, Pasche B. Tgf-beta signaling alterations and colon cancer. Cancer Treat Res. 2010;155:85–103.

    Article  CAS  PubMed  Google Scholar 

  178. Reynisdóttir I, Polyak K, Iavarone A, Massagué J. Kip/Cip and Ink4 cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev. 1995;9(15):1831–45.

    Article  PubMed  Google Scholar 

  179. Scandura JM, Boccuni P, Massagué J, Nimer SD. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci USA. 2004;101(42):15231–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. David CJ, Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19(7):419–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Massagué J. TGFbeta in cancer. Cell. 2008;134(2):215–30.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268(5215):1336–8.

    Article  CAS  PubMed  Google Scholar 

  183. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271(5247):350–3.

    Article  CAS  PubMed  Google Scholar 

  184. Zhang YE. Non-Smad Signaling Pathways of the TGF-β family. Cold Spring Harb Perspect Biol. 2017;9(2):a022129.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Calixto JB, Campos MM, Otuki MF, Santos AR. Anti-inflammatory compounds of plant origin. Part II. Modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Med. 2004;70(2):93–103.

    Article  CAS  PubMed  Google Scholar 

  186. Jiang Z, Cao Q, Dai G, Wang J, Liu C, Lv L, et al. Celastrol inhibits colorectal cancer through TGF-β1/Smad signaling. Onco Targets Ther. 2019;12:509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Chen CR, Tan R, Qu WM, Wu Z, Wang Y, Urade Y, et al. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, exerts antiepileptic effects via the GABA/benzodiazepine receptor complex in mice. Br J Pharmacol. 2011;164(5):1534–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Shen JL, Man KM, Huang PH, Chen WC, Chen DC, Cheng YW, et al. Honokiol and magnolol as multifunctional antioxidative molecules for dermatologic disorders. Molecules. 2010;15(9):6452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011;130(2):157–76.

    Article  CAS  PubMed  Google Scholar 

  190. Chei S, Oh HJ, Song JH, Seo YJ, Lee K, Lee BY. Magnolol suppresses TGF-β-Induced epithelial-to-mesenchymal transition in human colorectal cancer cells. Front Oncol. 2019;9:752.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Li J, Jiang K, Zhao F. Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA29b and downregulating matrix metalloproteinase2 expression. Mol Med Rep. 2015;12(4):5369–74.

    Article  CAS  PubMed  Google Scholar 

  192. Fei ZW, Qiu MK, Qi XQ, Dai YX, Wang SQ, Quan ZW, et al. Oxymatrine suppresses proliferation and induces apoptosis of hemangioma cells through inhibition of HIF-1a signaling. Int J Immunopathol Pharmacol. 2015;28(2):201–8.

    Article  CAS  PubMed  Google Scholar 

  193. Wang X, Liu C, Wang J, Fan Y, Wang Z, Wang Y. Oxymatrine inhibits the migration of human colorectal carcinoma RKO cells via inhibition of PAI-1 and the TGF-β1/Smad signaling pathway. Oncol Rep. 2017;37(2):747–53.

    Article  CAS  PubMed  Google Scholar 

  194. Liu X, Ji Q, Deng W, Chai N, Feng Y, Zhou L, et al. JianPi JieDu Recipe inhibits epithelial-to-mesenchymal transition in colorectal cancer through TGF-β/Smad mediated Snail/E-cadherin expression. Biomed Res Int. 2017;2017:2613198.

    PubMed  PubMed Central  Google Scholar 

  195. Dai Y, Wang H, Sun R, Diao J, Ma Y, Shao M, et al. Modified Shenlingbaizhu Decoction represses the pluripotency of colorectal cancer stem cells by inhibiting TGF-β mediated EMT program. Phytomedicine. 2022;103:154234.

    Article  CAS  PubMed  Google Scholar 

  196. Lin W, Zhuang Q, Zheng L, Cao Z, Shen A, Li Q, et al. Pien Tze Huang inhibits liver metastasis by targeting TGF-β signaling in an orthotopic model of colorectal cancer. Oncol Rep. 2015;33(4):1922–8.

    Article  CAS  PubMed  Google Scholar 

  197. Baretić D, Williams RL. PIKKs–the solenoid nest where partners and kinases meet. Curr Opin Struct Biol. 2014;29:134–42.

    Article  PubMed  Google Scholar 

  198. Murugan AK, mTOR. Role in cancer, metastasis and drug resistance. Semin Cancer Biol. 2019;59:92–111.

    Article  CAS  PubMed  Google Scholar 

  199. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10(3):457–68.

    Article  CAS  PubMed  Google Scholar 

  201. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–89.

    Article  CAS  PubMed  Google Scholar 

  202. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25(6):903–15.

    Article  CAS  PubMed  Google Scholar 

  203. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–75.

    Article  CAS  PubMed  Google Scholar 

  205. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–302.

    Article  CAS  PubMed  Google Scholar 

  206. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122–8.

    Article  CAS  PubMed  Google Scholar 

  207. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16(18):1865–70.

    Article  CAS  PubMed  Google Scholar 

  208. Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J. 2007;405(3):513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Harwood FC, Klein Geltink RI, O’Hara BP, Cardone M, Janke L, Finkelstein D, et al. ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer. Sci Adv. 2018;4(9):eaar3938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018;18(12):744–57.

    Article  CAS  PubMed  Google Scholar 

  211. Alqurashi N, Gopalan V, Smith RA, Lam AK. Clinical impacts of mammalian target of rapamycin expression in human colorectal cancers. Hum Pathol. 2013;44(10):2089–96.

    Article  CAS  PubMed  Google Scholar 

  212. Wang XW, Zhang YJ. Targeting mTOR network in colorectal cancer therapy. World J Gastroenterol. 2014;20(15):4178–88.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71(9):3246–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci USA. 2008;105(36):13544–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Gulhati P, Cai Q, Li J, Liu J, Rychahou PG, Qiu S, et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res. 2009;15(23):7207–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Hu X, Lin S, Yu D, Qiu S, Zhang X, Mei R. A preliminary study: the anti-proliferation effect of salidroside on different human cancer cell lines. Cell Biol Toxicol. 2010;26(6):499–507.

    Article  CAS  PubMed  Google Scholar 

  217. Wang J, Li JZ, Lu AX, Zhang KF, Li BJ. Anticancer effect of salidroside on A549 lung cancer cells through inhibition of oxidative stress and phospho-p38 expression. Oncol Lett. 2014;7(4):1159–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Hu X, Zhang X, Qiu S, Yu D, Lin S. Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells. Biochem Biophys Res Commun. 2010;398(1):62–7.

    Article  CAS  PubMed  Google Scholar 

  219. Fan XJ, Wang Y, Wang L, Zhu M. Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. Oncol Rep. 2016;36(6):3559–67.

    Article  CAS  PubMed  Google Scholar 

  220. Sa G, Das T. Anti cancer effects of curcumin: cycle of life and death. Cell Div. 2008;3:14.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Johnson SM, Gulhati P, Arrieta I, Wang X, Uchida T, Gao T, et al. Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res. 2009;29(8):3185–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Li X, Tian R, Liu L, Wang L, He D, Cao K, et al. Andrographolide enhanced radiosensitivity by downregulating glycolysis via the inhibition of the PI3K-Akt-mTOR signaling pathway in HCT116 colorectal cancer cells. J Int Med Res. 2020;48(8):300060520946169.

    Article  CAS  PubMed  Google Scholar 

  223. Shi MD, Liao YC, Shih YW, Tsai LY. Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Phytomedicine. 2013;20(8–9):743–52.

    Article  CAS  PubMed  Google Scholar 

  224. Lee YC, Cheng TH, Lee JS, Chen JH, Liao YC, Fong Y, et al. Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol Cell Biochem. 2011;347(1–2):103–15.

    Article  CAS  PubMed  Google Scholar 

  225. Li N, Zhang Z, Jiang G, Sun H, Yu D. Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway. Front Biosci (Landmark Ed). 2019;24(2):303–12.

    Article  PubMed  Google Scholar 

  226. Zhu X, Chen Y, Lin M, Huang B, Lin J. Qingjie Fuzheng Granule inhibits EMT and induces autophagy in colorectal cancer via mTOR signaling pathways. Evid Based Complement Alternat Med. 2021;2021:9950499.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Peng W, Zhang S, Zhang Z, Xu P, Mao D, Huang S, et al. Jianpi Jiedu decoction, a traditional Chinese medicine formula, inhibits tumorigenesis, metastasis, and angiogenesis through the mTOR/HIF-1α/VEGF pathway. J Ethnopharmacol. 2018;224:140–8.

    Article  PubMed  Google Scholar 

  228. Taipale J, Beachy PA. The hedgehog and wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54.

    Article  CAS  PubMed  Google Scholar 

  229. Geyer N, Gerling M. Hedgehog signaling in colorectal cancer: all in the stroma? Int J Mol Sci. 2021;22(3):1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Lin J, Chen Y, Cai Q, Wei L, Zhan Y, Shen A, et al. Scutellaria Barbata D Don inhibits Colorectal Cancer Growth via suppression of multiple signaling pathways. Integr Cancer Ther. 2014;13(3):240–8.

    Article  CAS  PubMed  Google Scholar 

  231. Parfitt JR, Driman DK. Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study. Hum Pathol. 2007;38(5):710–7.

    Article  CAS  PubMed  Google Scholar 

  232. Watt FM. Unexpected hedgehog-wnt interactions in epithelial differentiation. Trends Mol Med. 2004;10(12):577–80.

    Article  CAS  PubMed  Google Scholar 

  233. van den Brink GR, Hardwick JC. Hedgehog wnteraction in colorectal cancer. Gut. 2006;55(7):912–4.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Katoh Y, Katoh M. Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). Int J Mol Med. 2006;18(6):1019–23.

    CAS  PubMed  Google Scholar 

  235. Ruiz i Altaba A. Hedgehog signaling and the gli code in stem cells, cancer, and metastases. Sci Signal. 2011;4(200):pt9.

    PubMed  Google Scholar 

  236. Lees CW, Satsangi J. Hedgehog, paneth cells, and colon cancer: a cautionary note for the use of systemic agonists/antagonists. Gastroenterology. 2006;131(5):1657–8.

    Article  PubMed  Google Scholar 

  237. Chowdhury S, Pradhan RN, Sarkar RR. Structural and logical analysis of a comprehensive hedgehog signaling pathway to identify alternative drug targets for glioma, colon and pancreatic cancer. PLoS ONE. 2013;8(7):e69132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Ciucci A, De Stefano I, Vellone VG, Lisi L, Bottoni C, Scambia G, et al. Expression of the glioma-associated oncogene homolog 1 (gli1) in advanced serous ovarian cancer is associated with unfavorable overall survival. PLoS ONE. 2013;8(3):e60145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Wei L, Lin J, Xu W, Cai Q, Shen A, Hong Z, et al. Scutellaria barbata D. Don inhibits tumor angiogenesis via suppression of hedgehog pathway in a mouse model of colorectal cancer. Int J Mol Sci. 2012;13(8):9419–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Li L, Lin J, Sun G, Wei L, Shen A, Zhang M, et al. Oleanolic acid inhibits colorectal cancer angiogenesis in vivo and in vitro via suppression of STAT3 and hedgehog pathways. Mol Med Rep. 2016;13(6):5276–82.

    Article  CAS  PubMed  Google Scholar 

  241. Gerling M, Büller NV, Kirn LM, Joost S, Frings O, Englert B, et al. Stromal hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. Nat Commun. 2016;7:12321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Gulino A, Ferretti E, De Smaele E. Hedgehog signalling in colon cancer and stem cells. EMBO Mol Med. 2009;1(6–7):300–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Wu JY, Xu XF, Xu L, Niu PQ, Wang F, Hu GY, et al. Cyclopamine blocked the growth of colorectal cancer SW116 cells by modulating some target genes of Gli1 in vitro. Hepatogastroenterology. 2011;58(110–111):1511–8.

    CAS  PubMed  Google Scholar 

  244. Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1(6–7):338–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Fang XF, Cui ZJ. The anti-botulism triterpenoid toosendanin elicits calcium increase and exocytosis in rat sensory neurons. Cell Mol Neurobiol. 2011;31(8):1151–62.

    Article  CAS  PubMed  Google Scholar 

  246. Zhou Q, Wu X, Wen C, Wang H, Wang H, Liu H, et al. Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells. Biochem Biophys Res Commun. 2018;505(1):261–6.

    Article  CAS  PubMed  Google Scholar 

  247. Zhang T, Li J, Yin F, Lin B, Wang Z, Xu J, et al. Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene. 2017;36(47):6627–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Pei Z, Fu W, Wang G. A natural product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling. Biochem Biophys Res Commun. 2017;493(1):455–60.

    Article  CAS  PubMed  Google Scholar 

  249. Zhang M, Tao Z, Gao L, Chen F, Ye Y, Xu S, et al. Toosendanin inhibits colorectal cancer cell growth through the hedgehog pathway by targeting shh. Drug Dev Res. 2022;83(5):1201–11.

    Article  CAS  PubMed  Google Scholar 

  250. Sun Q, Yang H, Liu M, Ren S, Zhao H, Ming T, et al. Berberine suppresses colorectal cancer by regulation of hedgehog signaling pathway activity and gut microbiota. Phytomedicine. 2022;103:154227.

    Article  CAS  PubMed  Google Scholar 

  251. Khan I, Mahfooz S, Faisal M, Alatar AA, Ansari IA. Andrographolide induces apoptosis and cell cycle arrest through inhibition of aberrant hedgehog signaling pathway in colon cancer cells. Nutr Cancer. 2021;73(11–12):2428–46.

    Article  CAS  PubMed  Google Scholar 

  252. Zhu XQ, Yang H, Lin MH, Shang HX, Peng J, Chen WJ, et al. Qingjie Fuzheng Granules regulates cancer cell proliferation, apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via Sonic hedgehog pathway. J Gastrointest Oncol. 2020;11(6):1123–34.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Huang A, Cao S, Tang L. The tumor microenvironment and inflammatory breast cancer. J Cancer. 2017;8(10):1884–91.

    Article  PubMed  PubMed Central  Google Scholar 

  254. Johdi NA, Sukor NF. Colorectal cancer immunotherapy: options and strategies. Front Immunol. 2020;11:1624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Lozano T, Villanueva L, Durántez M, Gorraiz M, Ruiz M, Belsúe V, et al. Inhibition of FOXP3/NFAT Interaction enhances T cell function after TCR stimulation. J Immunol. 2015;195(7):3180–9.

    Article  CAS  PubMed  Google Scholar 

  256. Hassanzadeh-Kiabi N, Yáñez A, Dang I, Martins GA, Underhill DM, Goodridge HS. Autocrine type I IFN Signaling in dendritic cells stimulated with fungal β-Glucans or Lipopolysaccharide promotes CD8 T cell activation. J Immunol. 2017;198(1):375–82.

    Article  CAS  PubMed  Google Scholar 

  257. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol. 2014;44(6):1582–92.

    Article  CAS  PubMed  Google Scholar 

  258. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, et al. Concurrent infiltration by CD8 + T cells and CD4 + T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer. 2006;94(2):275–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514.

    Article  PubMed  PubMed Central  Google Scholar 

  261. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61.

    Article  CAS  PubMed  Google Scholar 

  262. Xu J, Song Z, Guo Q, Li J. Synergistic effect and molecular mechanisms of traditional Chinese medicine on regulating tumor microenvironment and cancer cells. Biomed Res Int. 2016;2016:1490738.

    Article  PubMed  PubMed Central  Google Scholar 

  263. Chen Y, Xie MY, Nie SP, Li C, Wang YX. Purification, composition analysis and antioxidant activity of a polysaccharide from the fruiting bodies of Ganoderma atrum. Food Chem. 2008;107(1):231–41.

    Article  CAS  Google Scholar 

  264. Zhang S, Nie S, Huang D, Li W, Xie M. Immunomodulatory effect of Ganoderma atrum polysaccharide on CT26 tumor-bearing mice. Food Chem. 2013;136(3–4):1213–9.

    Article  CAS  PubMed  Google Scholar 

  265. Wang CZ, Xie JT, Zhang B, Ni M, Fishbein A, Aung HH, et al. Chemopreventive effects of Panax notoginseng and its major constituents on SW480 human colorectal cancer cells. Int J Oncol. 2007;31(5):1149–56.

    CAS  PubMed  Google Scholar 

  266. Wang CZ, Luo X, Zhang B, Song WX, Ni M, Mehendale S, et al. Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells. Cancer Chemother Pharmacol. 2007;60(1):69–79.

    Article  PubMed  Google Scholar 

  267. Li XM, Yuan DY, Liu YH, Zhu L, Qin HK, Yang YB, et al. Panax notoginseng saponins prevent colitis-associated colorectal cancer via inhibition IDO1 mediated immune regulation. Chin J Nat Med. 2022;20(4):258–69.

    PubMed  Google Scholar 

  268. Wang X, Song ZJ, He X, Zhang RQ, Zhang CF, Li F, et al. Antitumor and immunomodulatory activity of genkwanin on colorectal cancer in the APC(Min/+) mice. Int Immunopharmacol. 2015;29(2):701–7.

    Article  CAS  PubMed  Google Scholar 

  269. Sun L, Yan Y, Chen D, Yang Y. Quxie capsule modulating gut microbiome and its association with T cell regulation in patients with metastatic colorectal cancer: result from a randomized controlled clinical trial. Integr Cancer Ther. 2020;19:1534735420969820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Liu J, Wang WP, Zhou YY. Observation on therapeutic effect of jianpi huoxue herbs combined with chemotherapy in treating post-operational colonic cancer patients. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005;25(3):207–9 Chinese.

    CAS  PubMed  Google Scholar 

  271. Wang ZJ, Wang XH, Li J, Zheng SH, Zhang FP, Hao SL, et al. The efficacy and safety of modified Gegenqinlian Fomular for advanced colorectal cancer (damp heat accumulation type): a multicenter randomized controlled trial. Med (Baltim). 2021;100(49):e27850.

    Article  CAS  Google Scholar 

  272. Tyagi A, Sharma AK, Damodaran C. A review on notch signaling and colorectal cancer. Cells. 2020;9(6):1549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by National Natural Science Foundation of China [Grant Number 82074352], and Natural Science Foundation of Shanghai Municipality [Grant Number 20ZR1458700]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

BH designed the study, coordinated technical support and funding. BH revised the manuscript. JFC performed the study, drafted the manuscript and designed the figures. SWW and ZMS participated the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bing Hu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, JF., Wu, SW., Shi, ZM. et al. Traditional Chinese medicine for colorectal cancer treatment: potential targets and mechanisms of action. Chin Med 18, 14 (2023). https://doi.org/10.1186/s13020-023-00719-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13020-023-00719-7

Keywords

  • Colorectal cancer
  • Traditional Chinese medicine
  • Signaling pathway
  • Mechanism of action