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Table 2 Relevant researches of NCTD on inhibiting proliferation and inducing apoptosis

From: Insight into norcantharidin, a small-molecule synthetic compound with potential multi-target anticancer activities

Cancers Cell lines Basic mechanisms Pathways Accompanying roles Experiment References
Leukemia K562 DNA synthesis inhibition; G2/M phase cell-cycle arrest    In vitro [18]
HL-60 G2/M cell-cycle arrest and apoptosis Inducing apoptosis via a caspases- dependent pathway, regulated by JNK activation signaling    [19]
Jurkat S phase cell-cycle arrest; activation of cytochrome c, caspase-9, -3; PARP cleavage Regulation of ATM With no effect on the viability of normal MNCs   [51]
Jurkat T G2/M phase cell-cycle arrest, down-regulating the expression of calcineurin, reducing calcineurin phosphatase activity Activation of P38 and ERK1/2 With no myelosuppression   [52]
HL-60 S and G2/M-phase arrest;DNA synthesis inhibition     [55]
Jurkat, Ramos Inducing the degradation of Cdc6     [65]
Jurkat Decreasing β-catenin protei Inhibiting Wnt/β-catenin signaling    [70]
HL-60 Inhibiting DNA replication, and induce apoptosis and caspase-3-dependent cleavage of Cdc6     [133]
MV4-11 Modulating the expression of several molecules, including HLF, SLUG, NFIL3 and c-myc   With no myelosuppression, inducing haemopoiesis In vivo
In vitro
[4]
K562, HL-60 DNA synthesis inhibition; G2/M phase cell-cycle arrest; producing interleukin (IL)-1β, colony stimulating activity (CSA) and tumor necrosis factor (TNF)-alpha Inhibition of PP2A Transient leukocytosis, less nephrotoxic and phlogogenic side-effects; stimulating hematopoiesis   [5]
L1210 Inhibiting the serine/threonine protein PP2A   Without myelosuppression, inducing haemopoiesis   [62]
Z138, Mino G2/M, G1 cell-cycle arrest, upregulating caspase-3, -8, and -9, suppressing NF-κB-regulated gene products, such as cyclin D1, BAX, survivin, Bcl-2, XIAP, and cIAP Inhibiting PI3K–Akt–NF-κB signaling pathway    [72]
Hepatocellular cancer HepG2 Xenograft growth inhibition   Prolonging host survival In vivo [50]
HepG2   Activation of ERK and JNK; modulation of NF-kappa B and AP-1   In vitro [6]
HepG2
Hep3B
Huh-7
M-phase cell-cycle arrest; phosphorylation of p21, Cdc25C; regulation of cyclin B1-associated kinase activity; phosphorylation of Bcl-2 and Bcl-X(L), activation of caspase-3, -9     [7]
SMMC-7721 BEL-7402 Inducing the activation of caspase-9, -3 and the cleavage of PARP, and downregulating the expression of Bcl-2, Bcl-X(L) and Mcl-1.     [11]
HepG2 Cytotoxic effect     [49]
Hep3B Downregulating TGF-β1 and Smad7, up-regulated Smad4 Altering TGF-β1/Smads signaling With cisplatin synergistic effect   [53]
HepG2 G2/M phase cell-cycle arrest, upregulating Bax, and downregulating Bcl-2   With EVO synergistic effect   [56]
BEL-7402 M phase cell-cycle arrest; decreasing Bcl-2 expression     [58]
HepG2 Inducing the degradation of Cdc6     [65]
HepG2 Inhibiting pre-RCs assembly, inducing degradation of Cdc6 and Mcm2, inhibiting the nuclear translocation of Mcm6, G1/S phase cell-cycle arrest, inhibiting DNA replication Inhibiting pre-RCs assembly via degrading initiation protein Cdc6, Mcm2, and Mcm6 With Cdc6 depletion synergistic effect   [66]
SMMC-7721 Upregulating caspase-3, cytochrome c, AIF, and Bax, downregulating Bcl-2 Activation of JNK and mitochondrial pathways    [134, 135]
HepG2 Downregulating Bcl-2, upregulating Bax, reduction of Bcl-2/Bax ratio Caspase-3, and -9 activities    [136]
HepG2 An increase in ROS production, loss of mitochondrial membrane potential and release of cytochrome c (cyto-c) from the mitochondria to the cytosol and downregulating Bcl-2, upregulating Bax levels. Increasing caspase-9, -3 and PARP Through ROS generation and mitochondrial pathway    [3]
Hep3B with deficiency of p53. G(2)M or G(0)G(1) phase cell-cycle arrest, activation of caspase-3, -10 Activation of a p53-independent pathway (caspase-3 and -10) via TRAIL/DR5 signal transduction    [137]
HepG2 Downregulating LC3-II, an autophagosome marker; upregulating Bax, cytochrome c, caspase-3, -9, PARP, ROS production; disrupting MMP Inhibiting autophagy via ROS generation and mitochondrial apoptosis pathway activation Atg5 siRNA enhances the anticancer action   [138]
HepG2 SMMC-7721 Inhibiting of Mcl-1, thus enhancing the release of cytochrome C, ABT-737, inducing apoptosis   Solving the ABT-737 drug resistance problem   [139]
SMCC-7721 SK-Hep-1 G2/M phase cell-cycle arrest; upregulating FAM46C, mitigating DEN-initiated HCC in mice; inhibiting Ras, p-MEK1/2, p-ERK1/2 Up-regulating FAM46C and inhibiting ERK1/2 signaling   In vivo
In vitro
[57]
Hep3B   Inhibiting PP5 via activating AMPK signaling    [140]
HepG2 HepG2/ADM hepatoma Hepal-1 Inhibiting cell viability, decreasing CD4+ CD25+ T cells, downregulating FoxP3 in vitro; suppressing tumor formation, downregulating Tregs, FoxP3, CTLA-4, TGF-β, IL-10 in vivo Downregulating regulatory T cells accumulation With CLSO synergistic effect   [141]
Gallbladder cancer GBC-SD Inhibiting PCNA and Ki-67 expression    In vitro [12, 67, 142]
GBC-SD Inhibiting PCNA, Ki-67, cyclin D1, Bcl-2, Survivin; upregulation of p27, Bax    In vivo
In vitro
[143, 144]
GBC-SD Inhibiting cyclin D1, Bcl-2, Survivin; upregulating p27, Bax; S phase cell- cycle arrest     [145]
Colorectal cancer Colo205
HT-29
SW480
G2/M phase cell-cycle arrest, activation of CD95 receptor/ligand and caspase 8    In vitro [59]
CT26 Cell cycle arrest in the S and G2/M phases, inducing anoikis-mediated apoptosis JNK activation    [60]
Six cell lines   Caspase-3, -8, -9 and MAPK activity    [68]
HT-29   Inhibiting integrin αvβ6-ERK    [146]
HCT116, HT29 G2/M phase cell-cycle arrest; downregulating EGFR, p-EGFR, c-Met, p-c-Met, and cyclinD1, Rb, CDK-4; increasing cleaved PARP and caspase-3 Affecting cell cycle- and apoptosis-related signaling Substituting for gefitinib   [147]
Breast cancer MCF-7 Repressing cell adhesion to platelets via downregulating α2 integrin Activating protein kinase C pathway via PP2A inhibition Inhibiting adhesion and migration In vitro [63]
MCF-7   Inhibiting MAPK and the dephosphorylation of erk1, 2    [148]
ER-HS-578T ER + MCF-7   Activation of MAPK and STAT pathways    [149]
Bcap-37 Increased ROS, decreased MMP, induced DNA damage and reduced G1, G2/M peak     [150]
MDA-MB-231 MDA-MB-468
BT-549
SKBR-3
MCF-7 BT474
  Dual inhibition of pAkt and pERK1/2 signaling   In vitro
In vivo
[16]
Highly-metastatic MDA-MB-231 G2/M phase cell-cycle arrest; up-regulating Bax, down-regulating Bcl-2, Bcl-2/Bax ratio, p-Akt, NF-kappaB Inhibiting the Akt and NF-kappaB signaling Suppressing tumor growth in vivo   [73]
Gastric cancer AGS G0/G1 phase cell-cycle arrest; increasing ROS production, cytochrome c, AIF and Endo G release; upregulating BAX, BID, caspase-3, -8, -9; downregulating MMP, caspase-4, -12 Through mitochondria- and caspase-dependent pathways   In vitro [151]
Melanoma A375-S2 Caspase-3, -9 activation and Bax upregulaton and Bcl-2 downregulation    In vitro [152]
A375-S2   Activation of JNK and p38 MAPK    [153]
U266 Potentializing the chemosensitivity to ADR Regulating NF-κB/IκBα signaling pathway and NF-κB-regulated gene products including survivin, Bcl-2, Bax and VEGF With ADR synergistic effect   [154]
WM115A, 1205Lu
Sbcl2, WM35
Increased cytochome c, Bax and caspase-3, decreased Bcl-2 and NF-κB2 Activation of a TR3 dependent pathway Improving survival In vitro
In vivo
[20]
Downregulating IKKα and p-IκBα, inducing the accumulation of IκBα and inhibiting activation of NF-κB, potentializing the chemosensitivity to BTZ Inhibiting NF-κB signaling pathway With BTZ synergistic effect   [155]
NSCLC EGFR mutation − A549
EGFR mutation + PC9
G2/M phase cell- cycle arrest, enhancing the anticancer effects of gefitinib and cisplatin   With gefitinib and cisplatin synergistic effect In vitro [54]
A549
H1299
Calu6
Repressing YAP and its downstream targets CYR61 and CTGF; arresting cell cycle, inducing senescence Repressing YAP signal pathway Inhibiting EMT, motile, invasion via enhancing E-cadherin and decreasing fibronectin/vimentin   [80]
A549 Downregulating Bcl-2, upregulating Bax, reducing Bcl-2/Bax ratio and viability   With trichostatin A, celecoxib, lovastatin, synergistic effect In vitro
In vivo
[157]
Oral cancer KB cell Induced significant cytotoxicity    In vitro [21]
SAS, Ca9-22 Activation of caspase-9, enhancing Bax, downregulating Bcl-2, Bcl-XL     [108]
Medulloblastoma DAOY, UW228 Loss of β-catenin activation; reduce of β-catenin expression Inhibition of Wnt/β-catenin signaling Ability to cross the blood–brain barrier In vitro
In vivo
[71]
Glioma U87, C6 Inhibiting phospho-MEK, phospho-ERK, Bcl-2 and Mcl-1 Blocking Raf/MEK/ERK pathway   In vitro [157]
Neuroblastoma SH-SY5Y   Inhibiting MAPK and the dephosphorylation of erk1,2   In vitro [148]
SK-N-SH Uppressing proliferation and cloning ability G2/M phase cell-cycle arrest; inducing mitophagy, autophagy; reducing MMP; downregulating cyclin B1, Cdc2, TOM20, SQSTM1/p62, p-AKT, mTOR; upregulating p21, beclin1, LC3-II, caspase-3, -9, p-AMPK; regulating Bax/Bcl-2, Bax/Mcl-1 The AMPK, AKT/mTOR, and JNK/c-Jun signaling pathways are widely involved in these processes via activation of JNK/c-Jun pathway    [158]
Cervical cancer HeLa Inducing the degradation of Cdc6.    In vitro [65]
HeLa Up-regulation of caspase-3, -8, -9, and Bax; down-regulation of Bcl-xL. Activation of ERK and JNK.    [159]
HeLa G2/M cell-cycle arrest; downregulating ΔΨ(m), Bcl-2, cyclin B and cdc2; upregulating Bax, cytochrome c, p21 and p-cdc25c Activating p38-NF-κB signaling pathway; p38-NF-κB-promoted mitochondria- associated apoptosis and G2/M cell cycle arrest    [160]
Bladder cancer TSGH 8301 S, G1phase cell-cycle arrest; upregulating caspase-3, -8, -9 and Fas, FasL, Bax, Bid, cytochrome c, and ROS production; downregulating ΔΨ(m), ERK, JNK, p38 Activation of ROS-modulated Fas receptor, caspse-3, -8, -9 mitochondrial -dependent and -independent pathways   In vitro [161]
Prostate cancer DU145 Inhibiting DNA replication and pre-RCs, inducing mitotic catastrophe Blocking ATR-dependent checkpoint pathway; degrading initiation protein Cdc6 With paclitaxel synergistic effec In vitro [162]
DU145 Downregulating PCNA, MnSOD; destructing MMP, ROS-mediated DNA damage; depleting ATP; activating AMPK ROS-mediated mitochondrial dysfunction and energy depletion    [163]
Increasing autophagy; inducing autophagic cell death, cell proliferation arrest; upregulating Beclin-1; suppressing miR-129-5p Inducing autophagy-related cell death through Beclin-1, upregulation by miR-129-5p suppression    [164]
22Rv1, Du145 Increased oligonucleosomal formation, PARP cleavage; upregulating cytochrome c, caspase-3, -8, -9, Fas, DR5, RIP, TRADD; increased ratios of pro-/anti-apoptotic proteins and decreased expression of IAP family member proteins, including cIAP1 and survivin Inducing both intrinsic and extrinsic apoptotic pathways    [165]
Mitochondria dysfunction, modulating Akt signaling via increasing nuclear translocation and interaction with Mcl-1 Suppressing Mcl-1 via epigenetic upregulation of miR-320d   In vitro
In vivo
[166]
Osteosarcoma 143B, SJSA Inducing G2/M cell cycle arrest Blocking the Akt/mTOR signaling pathway   In vitro [167]
MG63
HOS
The induction of autophagy, the triggering of ER stress and the inactivation of the c-Met/Akt/mTOR pathway The inhibition of the c-Met/Akt/mTOR signaling pathway   In vitro
In vivo
[22]
Glioblastoma RT-2
U251
G(2)/M phase arrest and post-G(2)/M apoptosis in RT-2 cell line   Adenoviral p53 gene therapy enhances chemosensitivity of tumor cells to NCTD. In vitro [168]
Giant cell tumor of bone (GCTB) Suppressing the PI3K/AKT signaling pathway through upregulating the expression of miR-30a Modulating the miR-30a/MTDH/AKT cell signaling pathway   In vitro [169]