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

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]