Table 3.
Summary for signaling pathways in preclinical stage for HCC therapy
| Signaling pathway | Target | Agent | Models | Level | Effect | Refs |
|---|---|---|---|---|---|---|
| PI3K/AKT/mTOR pathway | PI3K | DZW-310 | Hep3B, MHCC97H, Hep3B xenograft model | In vitro and in vivo | Attenuate angiogenesis and tumor growth | 243 |
| PI3K | Copanlisib | Huh7, HepG2 | In vitro | Induce apoptosis, inhibit cell growth, cell cycle arrest | 245,248 | |
| PI3K | LY294002 | MHCC97H, Huh7, Mahlavu | In vitro | Induce apoptosis, suppress cell growth | 244,246,655 | |
| PI3K | Wortmannin | Huh7, Mahlavu, HepG2 | In vitro | Induce apoptosis, suppress cell growth | 246 | |
| PI3K | Fenofbrate | Hep3B, Huh7, Hep3B xenograft model | In vitro and in vivo | Inhibit cell proliferation and migration, induce apoptosis, inhibit tumor growth | 656 | |
| AKT | AKT inhibitor VIII | Huh7, Mahlavu | In Vitro | Suppress cell growth, induce apoptosis | 246 | |
| AKT | Orlistat(FASN) or specific penetrating peptides | Akt knock-in mouse | In vivo | Suppress tumor growth | 657 | |
| mTOR | RAD001 (everolimus) | Patient-derived HCCs | In vivo | Growth inhibition | 658 | |
| mTOR | Metformin+sorafenib | HepG2, Bel-7402 xenograft model | In vitro and in vivo | Growth inhibition | 659 | |
| mTOR | miRNA-199a-3p | Huh7 xenograft model | In vivo | Growth inhibition and survival prolong | 660 | |
| mTOR | miRNA-99a | SMMC-LTNM | In vivo | Decreased tumor size | 661 | |
| PI3K/mTOR | BEZ235 | Hep3B, Huh7, PLC/RLF5 | In vitro | Growth-inhibitory, induce apoptosis | 247 | |
| AKT/mTOR | Lenvatinib | Hep3B, HepG2 | In vitro | Inhibit cell proliferation and migration | 662 | |
| AKT/mTOR | ZJQ-24 | HepG2 xenograft model | In vivo | Inhibits angiogenesis, induce apoptosis and growth inhibition | 663 | |
| PI3K/AKT | Artemisia rupestris L.(ARL) | HepG2 | In vitro | Restrict HepG2 cell proliferation, apoptosis, migration and invasion | 664 | |
| PI3K/AKT | YangzhengXiaoji capsue (YXC) | MHCC97H, HCCLM3, HepG2, Huh7, liver xenograft tumor model of MHCC 97H and HCCLM3 | In vitro and in vivo | Inhibit HCC tumor growth | 665 | |
| mTOR+VEGF | Rapamycin+bevacizumab | HepG2 xenograft model | In vivo | Growth inhibition and survival prolong | 666 | |
| PI3K/AKT/mTOR | Suaeda vermiculata Forssk (SVE) | DEN-treated rats | In vivo | Suppress the development of HCC | 667 | |
| PI3K/AKT/mTOR | Isoliquiritigenin (ISL) | SMMC-7721, MHCC97H, SMMC-7721 xenograft model | In vitro and in vivo | Induce apoptosis and autophagy and tumor growth | 655 | |
| Wnt/β-catenin pathway | PORCN | LGK-974(WNT-974), ETC-159 | HepG2 cell lines | In vitro | Enhances radiosensitivity | 668 |
| TNKS | XAV939 or WXL-8 | HepG2 and HepG2 xenograft model | In vitro and in vivo | Growth inhibition | 334 | |
| β-catenin/TCF | Fungal derivatives (PKF 115-854, CGP0449090) | HCC cell lines(HepG2, Hep40, Huh7), HepG2 xenograft model Hep3B, MHCC97, and SK-Hep-1 | In vitro and in vivo | Growth inhibition | 332,333 | |
| ß-catenin | RNAi (siRNA) | HuH-6 and HepG2 cell lines | In vitro | Proliferation inhibition | 336 | |
| ß-catenin | RNAi (siRNA) | HepG2 cell lines | In vitro | Apoptosis and angiogenesis gene expression | 335 | |
| ß-catenin | LNA-si-β-catenin | GOF Ctnnb1-mutant mouse HCC model induced by diethylnitrosa mine (DEN) and phenobarbita (PB) | In vivo | Decreased cell proliferation and increased cell death | 337 | |
| ß-catenin | siCTNNB1-LNP | Met/mutant-β-catenin HTV mice model | In vivo | Reduced tumor cell proliferation and viability | 307 | |
| BCL9 and β-catenin, PD-1/PD-L1 | sBBI&PDP nanoparticles | Orthotopic homograft mice model of HCC and a PDX HCC model | In vivo | Antitumor efficacy with a favorable biosafety profile | 669 | |
| JAK-STAT pathway | JAK2 | Dehydrocrenatidine (DHCT) | HepG2 xenograft | In vivo | Induced invasion and CSC phenotypes | 670 |
| JAK1/2 | Ruxolitinib(INC424) | Huh7, SNU182, SNU423 | In vitro | Inhibit cell proliferation, promote apoptosis | 272 | |
| JAK1,2,3 | CIMO | Huh7 orthotopic xenograft | In vivo | Reduced tumor growth | 671 | |
| STAT3 | Leonurine | HepG2, Hep3B, and HCCLM3 cells | In vitro | Induced apoptosis and also significantly potentiated the cytotoxic effect of paclitaxe l, doxorubicin, and sorafenib. | 672 | |
| STAT3 | WP1066 | Bel7402 cell lines | In vitro | Inhibit cell migration and invasion through EMT | 274,673 | |
| STAT3 | Stattic | HepG2, Bel-7402, SMMC-7721 cell lines | In vitro | Enhance radiosensitivity, reduce radio induced migration and invasion | 674 | |
| STAT3 | Cryptotanshinone (CTS) | MHCC97H,L02 and L02 xenograft model | In vitro and in vivo | Inhibit cell migration, invasion, carcinogenesis; | 675 | |
| Hepa1-6 model | Inhibit tumor growth and activation of macrophages and polarized mouse bone marrow-derived macrophages (BMM) toward anM1 phenotype; synergy with anti-PDL1 | 676 | ||||
| STAT3 | Napabucasin | Hepa1-6 xenograft | In vivo | Reduced tumor growth | 677 | |
| JAK/STAT | AZ960, TG101209 | Akt/β-catenin hepatic tumor mouse model and tumorspheres | In vivo and in vitro | Abrogate cell proliferation, n regulating the self-renewing | 678 | |
| JAK1, STAT3 | CoL-EtOH | HepG2 cell lines | In vitro | Impeded the viability | 679 | |
| JAK1, STAT3 | Nitidine chloride | HepG2 xenograft | In vivo | Reduced tumor volume | 680 | |
| JAK2/STAT3 | Etomidate | HepG2 xenograft | In vivo | Inhibition of tumor growth Increase in animal survival | 681 | |
| EphB4 receptor(JAK2, STAT3) | Cantharidin | SMMC-7721 | In vivo | Reduced tumor volume | 682 | |
| IL-6 (STAT3) | miR-515-5p | HepG2 xenograft | In vivo | Inhibit migration and invasion | 683 | |
| miR-221-3p(STAT3) | C1QTNF1-AS1 | HepG2 and Huh7 xenograft | In vivo | Reduced tumor volume | 261 | |
| Hedgehog pathway | Smo | Vismodegib (GDC-0449) | HBxTg mice, Orthotropic Transplantation mice model of hepatoma Mistheton Lectin-1 cell | In vivo | Suppress hepatic tumor development | 684,685 |
| Smo | Cyclopamine | HCC cell lines (Hep3B, Huh7, PLC/PRF5), Orthotropic Transplantation mice model of hepatoma Mistheton Lectin-1 cells | In vitro and in vivo | Decreased tumor size | 367 | |
| Gli | GANT61 | Human HCC cell lines and xenograft model of Huh 7, cd44+Patient-derived organoids | In vitro and in vivo | Inhibit proliferation, migration, in vivo growth, drug resistance(sorafenib, 5-FU, doxorubicin, and cisplatin resistance) | 368–372 | |
| Gli | RNAi | Huh7 cell lines | In vitro | Reverse sorafenib, 5-FU, doxorubicin, and cisplatin resistance | 369 | |
| Gli | NanoHHI | HCC cell lines(Huh7,MHCC97L), subcutaneous and orthotopic xenograft model of Huh7 | In vivo | Growth inhibition and antimetastatic effects in vivo | 374 | |
| SULF2 | OKN-007 | HCC cell lines (Huh7, Hep3B) and Huh7 xenografts | In vivo and in vitro | Promoted tumor cell apoptosis and inhibited cell proliferation, viability, and migration, inhibit in vivo tumor growth | 377 | |
| Shh, Smo and Gli1 | Taccalonolide A | HCC cell lines | In vitro | Reduce viability | 376 | |
| Unselective (Shh, Gli, Smo, etc) | Itraconazole | DEN-induced HCC rats model | In vivo | Anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects | 686 | |
| Hippo pathway | TAZ((WWTR1) | Statins(fluvastatin, simvastatin) | HLF and HuH1 cell lines | In vitro | Inhibit cell proliferation | 400 |
| MST1, YAP | Salvianolic acid B (SalB) | HepG2, DEN/CCl4/C2H5OH-induced HCC model | In vitro and in vivo | Inhibit cell proliferation and migration, tumorigenesis in vivo | 401 | |
| Tankyrase | G007-LK | c-Met/sgAxin1 HCC mouse model | In vivo | Synergizes with cabozantinib leading to tumor regression | 390 | |
| LATS | NIBR-LTSi | Mice with extended hepatectomy | In vivo | Accelerates liver regeneration | 403 | |
| Notch pathway | γ-Secretase | Ginsenoside (Rg3) | HepG2, Huh7 and Huh7 xenograft mouse | In vitro and in vivo | Synergistic antitumor with sorafenib via AKT | 437 |
| ADAM17 | ZLDI-8 | HepG2, Hep3B, Hep3B xenograft mouse | In vitro and in vivo | Synergistic antitumor with sorafenib | 438 | |
| Notch2 | Antagonistic antibody | AKT/Ras HTV mice model | In vivo | Decreased tumor burden | 426 | |
| Epigenetics | Pan-HDAC | Panobinostat | HepG2, Hep3B, HepG2 xenografts | In vitro and in vivo | Delayed growth and prolonged survival | 687 |
| Pan-HDAC | Panobinostat | HCC xenografts | In vivo | Combination with sorafenib decreased tumor volume and increased surviva | 688 | |
| Pan-HDAC | Suberanilohydroxamic A cid (SAHA) | LCL-PI 11 | In vitro | Growth inhibition and apoptotic induction | 689 | |
| Pan-HDAC | HL23 | PLC/PRF/5, cMHCC97L orthotopic HCC mouse model | In vitro and in vivo | Suppressed HCC progression and metastasis | 690 | |
| Pan-HDAC | MPT0G009 | Hep3B cell lines and xenograft models | In vitro and in vivo | Induced apoptosis and growth arrest | 691 | |
| Pan-HDAC | AR-42 | Huh7 cell lines and xenograft models | In vitro and in vivo | Radiosensitize in inhibition of HCC cell growth | 692 | |
| Pan-HDAC | Belinostat | Subcutaneous Hepa129 murine HCC model | In vivo | Enhanced anti-tumor efficacy of checkpoint inhibitors | 464 | |
| Pan-HDAC | Quisinostat | HCCLM3 xenograft model | In vitro and in vivo | Synergetic with sorafenib, facilitated G0 G1 cycle arrest and apoptosis | 693 | |
| HDAC1 | Trichostatin A | Huh7, HLE, HLF, HepG2, HepG2 xenografts | In vitro and in vivo | Inhibit cell proliferation, induce apoptosis Sensitize HCC cells to enhanced NK-cell mediated killing | 694,695 | |
| HDAC-3,6,8 | Droxinostat | SMMC-7721 and HepG2 | In vitro | Induce apoptosis | 696 | |
| HDAC8 | PCI-34051 | Hepa1-6 orthotopic HCC mouse model | In vivo | Elevated intratumoral CD8+ T cell infiltration, reduced tumorigenicity, d elevated intratumoral CD8+ T cell infiltration, reduced tumorigenicity alone or combined wth anti-PDL1 | ii473 | |
| Class I and class II HDAC | Valproic Acid | HepG2, Huh7 | In vitro | TRAIL-induced apoptosis and chemotherapy sentization | 697,698 | |
| Class I, class IIa and IV HDAC | Resminostat | Huh7, HCC-LM3, SK-Hep-1, Huh7 xenografts, HepG2, Hep3B, SMMC-7721, patient-derived primary HCC cells, DEN-induced HCC mouse mode | In vitro and in vivo | Activate apoptosis | 699–701 | |
| BRD | JQ-1 | HepG2, N-Ras/c-Myc HTVi HCC mouse model; Huh7, Hep3B and Hepa129;DEN/CDAHFD diet-induced mouse model of NASH-driven HCC | In vitro and in vivo | Synergetic with anti-PD1 antibody; Reduce tumor aggressiveness | 474–476 | |
| BRD4 | i-BET762 | Hepa1-6 orthotopic HCC mouse model | In vivo | Combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumor eradication and prolonged survival in the fibrotic-HCC mouse model. | 477 | |
| DNMT | Guadecitabine (SGI-110) | SNU398, HepG2 and SNU475 | In vitro | Anti-proliferation effects | 702 | |
| DNMT | 5-Aza-CdR (DAC) | SNU5, HepG126, and SNU2 | In vitro | Synergistic anti-tumor effect with EZH2 inhibitor (GSK1 26) | 472 | |
| G9a and DNMT1 | CM-272 | HepG2, PLC/PRF-LX2 mixed tumors | In vitro and in vivo | Inhibit cell proliferation and tumor growth | 469 | |
| G9a (EHMT2) | UNC0638, BIX01294 | BEL7402, SMMC-7721 | In vitro | Inhibit cell growth | 470 | |
| EZH2 | GSK343 | Hepa1-6 subcutaneous xenograft mode | In vivo | Tumor suppression | 468 | |
| P53 signaling | wildtype p53 | p53 mRNA delivery by nanoparticles | Hep3B cell lines and xenograft models, p53-null orthotopic and ectopic models of murine HCC | In vitro and in vivo | Tumor suppression, synergetic with anti-PD1 antibody | 495,496 |
| wildtype p53 | Adiponectin | HepG2 | In vitro | Suppress tumor through apoptosis | 497 | |
| mutp53-Y220C | SLMP53-2 | Huh7 cell lines and xenograft models | In vitro and in vivo | Growth inhibition, synergistic effect with sorafenib | 498 | |
| p53-bax | Oleanolic acid | HepG2 cell lines and wildtype mice | In vitro and in vivo | Enhanced apoptosis and reduced hepatotoxicity, synergistic effect with cisplatin | 499 | |
| p53-bax | Acetylshikonin | SMMC-7721 cell lines and H22 mouse model | In vitro and in vivo | Growth inhibition, enhanced apoptosis | 500 | |
| Bcl-2 | ABT-199 | Huh7, Hep3B, HepG2 cell lines | In vitro | Induce cell death in combination with MIK665 | 505 | |
| Bcl-2 | Obatoclax | HepG2 and Hepa1-6 cell lines, Hepa1-6 and Hepa1c1c7 xenograft models | In vitro and in vivo | Tumor suppression, synergetic with anti-PD1 antibody | 504 | |
| Fas/FasL | Scutellarein | Hep3B cell lines | In vitro | Growth inhibition, induce apoptosis and cell cycle arrest | 506 | |
| Caspase 8 | Garciniaxanthone I | HepG2 cell lines | In vitro | Induce apoptosis and inhibit migration | 507 | |
| Cyt-C | Compound 19b | Huh7, Hep3B, HepG2 cell lines | In vitro | Induce apoptosis | 508 | |
| Cyt-C | Lycorine | HepG2 cell lines and xenograft models | In vitro and in vivo | Induced apoptosis | 509 | |
| CDK4/6 | Palbociclib(PD-0332991) | PLC/PRF/5, HepG2, Hep3B | In vitro | Growth inhibition | 513 | |
| CDK4/6 | Abemaciclib, ribociclib | HUH7, SNU398, HepG2 | In vitro | Simultaneous combination of abemaciclib with lenvatinib reduced 3D cell growth, and impaired colony formation and cell migration | 514 |