. 2020 May 29;15:55. doi: 10.1186/s13020-020-00338-6

Table 2.

Relevant researches of NCTD on inhibiting proliferation and inducing apoptosis

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]
	WM115A, 1205Lu Sbcl2, WM35	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]
Oral cancer	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]
Neuroblastoma	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]
	DU145	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]
	22Rv1, Du145	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]
Osteosarcoma	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)	RT-2 U251	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]