Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches

Farzaneh, Zahra; Vosough, Massoud; Agarwal, Tarun; Farzaneh, Maryam

doi:10.1186/s12935-021-01924-w

Cancer Cell International

Table 1 The effects of small molecules on signaling pathways related to HCC

From: Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches

Pathway	Small molecule		Target	Cell line	Animal model	Result	Ref.
TGF-B	Galunisertib (LY2157299)	Phase II/III in HCC NCT01722825	Receptor	SK-HEP1, HepG2, Hep3B, Huh7	–	Decrease proliferation, increase apoptosis In combination with Sorafenib, the anti-cancer effects was increased in concentration dependent manner	[42]
TGF-B	PD98059	–	ERK	HepG2	7 × 10⁵ HepG2 intraperitoneal into nude mice	Inhibit proliferation, migration, invasion, and tumor growth –	[45]
Wnt	IC-2	–	TCF/β-catenin	Huh7, HepG2, HLF	Huh7 spheres to flank of NOD/SCID mice	Decrease the CSC subpopulation –	[63]
Wnt	CGP049090/ PKF115-854	-/ PMID: 23,626,717	TCF/β-catenin	Huh7, HepG2,	1 × 10⁷ HepG2 subcutaneously to Nude mice	Induce apoptosis, cell cycle arrest, inhibit tumor growth –	[191]
Hh	Cyclopamine	Phase III http://www.biomath.info/Protocols/Duke/docs/HermanSara.pdf	SMO receptor	Huh7, PLC, SM-7721,	5 × 10⁶ Mistheton Lectin-1 into the left liver of mice	Induce apoptosis, inhibit tumor growth -/-	[74, 192]
	GANT61	–	Gli	Huh7, Hep3B, HepG2	1 × 10⁷ Huh7 cells to flank of SCID mice	Induce the autophagy and apoptosis, Inhibit the HCC tumor growth Similar to Sorafenib, increase the apoptosis	[71]
	GDC-0449	Phase II https://clinicaltrials.gov/ct2/show/NCT00636610	SMO receptor	Huh7, MHCC97	5 × 10⁶ MHCC97subcutaneously to syngeneic rat	Decrease the angiogenesis Combined with Sorafenib can modulate the VEGF expression	[69]
Notch	PF-4014	Phase II https://clinicaltrials.gov/ct2/show/NCT02299635?cond=PF-03084014&draw=2&rank=1	γ-secretase	MHCC97, Huh7	1 × 10⁶ MHCC97-H or 4 × 10⁵ CSC subcutaneously to nude or SCID mice then tumor cubes were then implanted into nude mice liver lobes	Inhibited the proliferation of HCC and CSC self-renewal, decrease the tumor volume, and suppress the liver tumor metastasis PF-03084014 in combination with cisplatin or doxorubicin increase the anti-cancer effects	[80]
Notch	GSI	Phase II https://clinicaltrials.gov/ct2/show/NCT01196416	γ-secretase	Bel7404, HepG2	–	Decrease the HCC proliferation and colony formation –	[81]
EGF	Brivanib	Phase II https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728988/	Tyrosine kinase receptor	Hep3B, HepG2, Huh7	DEN to rat	HCC apoptosis, cell cycle arrest, inhibit the liver tumor growth –	[193]
	U0126	–	Erk	HCCLM3, HepG2	–	Decrease proliferation –	[87]
	BEZ-235/ SHBM1009	PhaseII, https://clinicaltrials.gov/ct2/show/NCT01288092/-	PI3K	HCCLM3, HepG2	–	Decrease proliferation –	[87]
HGF	PHA665752	–	c-met	MHCC97l Huh7, Hep3B	3 × 10⁵ MHCC97 subcutaneously to nude mice	Inhibit proliferation, tumor growth, and CSC, increase apoptosis –	[93]
	AMG 337	Phase I/II, https://clinicaltrials.gov/ct2/show/NCT02096666	c-met	MHCC97, HCCLM3, Hep3B, SNU, JHH5	human primary HCC tumor tissues Subcutaneously injecting nude mice	Decrease proliferation, tumor growth –	[95]
	Indo5	–	c-met	HepG2, A549, SMMC-7721 MHCC97H	2 × 10⁶ HepG2, 4 × 10⁶ MHCC 97H, 4 × 10⁶ MHCC 97 L, 2 × 10⁶ A549 cells, or 5 × 10⁶ SMMC-7721 subcutaneously to flank of SCID mouse MHCC97H subcutaneously to flank of SCID mouse then insert tumor into liver	Inhibit proliferation, migration, and metastasis Similar or better result in animal model recovery compared with Sorafenib In contrast to Sorafenib without body weight lost	[94]
VEGF	Bufalin	–	VEGFR/EGFR	SMMC-7721, PLC	5 × 10⁶ SMMC-7721 subcutaneously to flank of nude mice	Inhibit angiogenesis, HCC migration, and proliferation The anti-cancer effects of Bufalin improved in combination with Sorafenib	[194]
Stat3	Jaki	–	Jak	Huh7, Hep3B, HepG2	–	Increase apoptosis Sensitize the HCC to anti-cancer effects of Sorafenib	[112]
	C188-9	–	Stat3	PLC, HepG2, Huh7	HepPten- mice Non-alcoholic steatohepatitis (NASH)	Decrease the survival of HCC, reduce the HCC proliferation, decrease the secretion of inflammatory factors –	[113]
	S3i-201	–	Stat3	Huh7, Hep3B, HepG2	–	Induce HCC apoptosis and enhance the Sorafenib effects Increase the anti-cancer effects of Sorafenib	[112]
	UA	–	Stat3	Huh7, HepG2, SM-7721, Hep3B	1 × 10⁷ HepG2 subcutaneously into flank of nude mice	Increase the HCC apoptosis, inhibit the tumor growth –	[114]
	2-Ethoxystypandrone		Stat3	HepG2	–	Induce apoptosis and cell cycle arrest, inhibit the CSC self-renewal –	[115]
YAP/TAZ	verteporfin	–	YAP/TEAD	Huh7, MLP29	IP injection of DENA to Rats	Decrease the colony formation, survival, and tumor colony –	[125]
HIF	PT2385	Phase I, https://clinicaltrials.gov/ct2/show/NCT02293980	HIF-2a	HepG2, Sk-hep1	of 1 × 10⁶ SK-Hep1 intrahepatic injections to nude mice	Increase the efficiency of Sorafenib treatment, decrease invasion and survival Increase the anti-cancer effects of Sorafenib	[136]
Cell cycle	Dinaciclib	Phase I https://clinicaltrials.gov/ct2/show/NCT01711528?cond=Dinaciclib&draw=2&rank=2	Cdk1,2,5,9	Hep3B, HLE	1 × 10⁶ Huh7 cells or 2 × 10⁶ PLC BALB/c subcutaneously to nude mice	Decrease the colony formation, survival, induce cell cycle arrest, decrease the tumor size Similar results with Sorafenib	[143]
Cell cycle	Ribociclib	–	CylinD/cdk4,6	Huh7, HepG2, Hep3B, PLC	–	Decrease cell proliferation Synergist effects with Sorafenib and anti-cancer effects on Sorafenib resistance-HCC lines	[144]
Apoptosis	Tumstatin	–	Akt/mTOR	Huh7, Hep3B	5 × 10⁶ Hep3B cells subcutaneously to armpit of nude mice	Induce apoptosis, cell cycle arrest, autophagy, decrease the tumor growth, increase the apoptotic proteins –	[171]
	Brivanib	–	FGF, VEGF, P53	Huh7, HepG2, Hep3B,	Rat with DENA	Induce cell cycle arrest and apoptosis –	[82]
	Nutlin	–	MDM	Huh7, SM-7721,	–	Inhibit proliferation and survival –	[161]
	Rubone	–	miR-34a, Bcl2, cyclinD	HepG2, HuH7, Hep3B	5 × 10⁶ HepG2 to dorsal flanks of nude mice	Activate the miR34 and inhibit the TGF-B pathway and tumor growth Stronger than Sorafenib	[162]
Autophagy	Verteporfin		lysosom	HepG2, HuH7	2 × 10⁶ HepG2 to dorsal flanks of nude mice	Induce autophagy Increase the anti-cancer effects with Sorafenib	[173]
	NVP-BGT226	–	mTOR	Hep3B, HepG2, SNU475, Mahlavu	–	Induce autophagy More sensitive to Sorafenib	[174]
	Mitoxantrone	–	mTOR	HepG2, HuH7	–	Induce autophagy –	[170]
ROS	Propyl gallate	–	ROS formation	HepJ5, Hep3B, Mahlava	200 HepJ5 or Hep3B injected to yolk of zebrafish embryos	Decrease proliferation, increase apoptosis and autophagy –	[186]
ROS	Auranofin	–	TXNRD	Hep3B	–	Increase apoptosis –	[184]

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