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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
Receptor SK-HEP1, HepG2, Hep3B, Huh7 Decrease proliferation, increase apoptosis
In combination with Sorafenib, the anti-cancer effects was increased in concentration dependent manner
PD98059 ERK HepG2 7 × 105 HepG2 intraperitoneal into nude mice Inhibit proliferation, migration, invasion, and tumor growth
Wnt IC-2 TCF/β-catenin Huh7, HepG2, HLF Huh7 spheres to flank of NOD/SCID mice Decrease the CSC subpopulation
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
Hh Cyclopamine Phase III
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
GDC-0449 Phase II
SMO receptor Huh7, MHCC97 5 × 106 MHCC97subcutaneously to syngeneic rat Decrease the angiogenesis
Combined with Sorafenib can modulate the VEGF expression
Notch PF-4014 Phase II
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
GSI Phase II
γ-secretase Bel7404, HepG2 Decrease the HCC proliferation and colony formation
EGF Brivanib Phase II
Tyrosine kinase receptor Hep3B, HepG2, Huh7 DEN to rat HCC apoptosis, cell cycle arrest, inhibit the liver tumor growth
U0126 Erk HCCLM3, HepG2 Decrease proliferation
BEZ-235/ SHBM1009 PhaseII, PI3K
HGF PHA665752 c-met MHCC97l Huh7, Hep3B 3 × 105 MHCC97 subcutaneously to nude mice Inhibit proliferation, tumor growth, and CSC, increase apoptosis
AMG 337 Phase I/II, c-met MHCC97, HCCLM3, Hep3B, SNU, JHH5 human primary HCC tumor tissues Subcutaneously injecting nude mice Decrease proliferation, tumor growth
Indo5 c-met HepG2, A549, SMMC-7721
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
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
Stat3 Jaki Jak Huh7, Hep3B, HepG2 Increase apoptosis
Sensitize the HCC to anti-cancer effects of Sorafenib
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
S3i-201 Stat3 Huh7, Hep3B, HepG2 Induce HCC apoptosis and enhance the Sorafenib effects
Increase the anti-cancer effects of Sorafenib
UA Stat3 Huh7, HepG2, SM-7721, Hep3B 1 × 107 HepG2 subcutaneously into flank of nude mice Increase the HCC apoptosis,
inhibit the tumor growth
2-Ethoxystypandrone   Stat3 HepG2 Induce apoptosis and cell cycle arrest, inhibit the CSC self-renewal
YAP/TAZ verteporfin YAP/TEAD Huh7, MLP29 IP injection of DENA to Rats Decrease the colony formation, survival, and tumor colony
HIF PT2385 Phase I, 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
Cell cycle Dinaciclib Phase I 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
Ribociclib CylinD/cdk4,6 Huh7, HepG2, Hep3B, PLC Decrease cell proliferation
Synergist effects with Sorafenib and anti-cancer effects on Sorafenib resistance-HCC lines
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
Brivanib FGF,
Huh7, HepG2, Hep3B, Rat with DENA Induce cell cycle arrest and apoptosis
Nutlin MDM Huh7, SM-7721, Inhibit proliferation and survival
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
Autophagy Verteporfin   lysosom HepG2, HuH7 2 × 106 HepG2 to dorsal flanks of nude mice Induce autophagy
Increase the anti-cancer effects with Sorafenib
NVP-BGT226 mTOR Hep3B, HepG2, SNU475, Mahlavu Induce autophagy
More sensitive to Sorafenib
Mitoxantrone mTOR HepG2, HuH7 Induce autophagy
ROS Propyl gallate ROS formation HepJ5, Hep3B, Mahlava 200 HepJ5 or Hep3B injected to yolk of zebrafish embryos Decrease proliferation, increase apoptosis and autophagy
Auranofin TXNRD Hep3B Increase apoptosis