Introduction
S. No. | Name of the drug | Target molecule | Mechanism | Limitation | Year and references |
---|---|---|---|---|---|
1 | Tamoxifen | Antagonist of estrogen receptor | To inhibit P-glycoprotein-mediated drug resistance | Minimum effect | 2000 [88] |
2 | 5-Fluoracil | Thymidylate synthase | Incorporated its metabolites into RNA and DNA | Requires co-treatment with leucovorin and methotrexate, to increase the anticancer activity of 5-Fu | 2003 [89] |
3 | Thalidomide | VEGF, inhibits TNF-α synthesis, inhibition of Ikβ kinase activity | Anti-angiogenic activity and immune-modulatory | Fatigue, somnolence, constipation | |
4 | Octreotide | Analogue of somatostatin receptors | Anti-tumor effect. | Somatostatin receptor type 2 (SSTR2) was found in some but not all patients with HCC | |
5 | Sorafenib | Raf, VEGFR2, VEGFR3, PDGFRs | Inhibits tumor angiogenesis by blocking the activation of the tyrosine kinase receptors | Hypertension, diarrhea, proteinuria, skin-related toxicities, an increased risk for thromboembolism and bleeding events | |
6 | Sunitinib | PDGFRs, KIT, RET, and FLT3 | Inhibits tumor angiogenesis by blocking the activation of the tyrosine kinase receptors | Modest clinical efficacy | 2009 [94] |
7 | Bevacizumab | VEGF | Blocks VEGF binding to its receptor | Low rate of response, gastrointestinal bleeding, including variceal bleeding | 2009 [95] |
8 | Erlotinib, gefitinib and cetuximab | EGFR | Tyrosine kinase inhibitor, acts on the epidermal growth factor receptor (EGFR) | Minimum effect | 2009 [96] |
9 | Doxorubicin | DNA topoisomerase II inhibitors | Induce histone eviction | The use of single agents in therapy is practically non-existent currently because of its erratic and low response | 2013 [97] |
10 | Cisplatin | DNA | Cross link with purine causes DNA damage and ultimately induces apoptosis | Allergic reactions, gastrointestinal disorders, decrease immunity to infections, kidney problems, hemorrhage | 2014 [98] |
11 | Oxaliplatin | DNA | Binds to guanine and cytosine leading to cross-linking of DNA | Increase autophagy level results in a tumor resistance Reduction of DYRK2 promotes cell proliferation, and resistance to Oxaliplatin | 2016 [99] |
Various mechanism of chemoresistance in HCC cells
Reduced drug uptake, efflux of drugs and drug metabolism
S. No. | Transporter | Mode of action | Up-regulated or down-regulated | References |
---|---|---|---|---|
1 | MDR1 (ABCB1 or P-glycoprotein), MRP1 (ABCC1), MRP2 (ABCC2), MRP3(ABCC3) and ABCG2 | Extrudes unrelated anti-tumoral agents like anthracyclines, taxanes, vinca alkaloids etc. from the cell | Up regulated | |
2 | OATP1B1 and OATP1B3 | Transports anti-tumor drugs inside the cells | Down regulated | |
3 | SLC28 and SLC29 | Uptake of nucleoside derived anticancer drugs | Down regulated | [103] |
4 | Organic cationic transporter-1 (OCT1) | Uptake of tyrosine kinase inhibitors | Down regulated; hyper-methylation of the SLC22A1 promoter | [104] |
DNA repair pathway aberrations and chemoresistance in HCC
S .No. | DNA repair enzyme | Therapy given | Repair mechanism involved | Reference |
---|---|---|---|---|
1 | ERCC-1 | Platinum based anti-cancer agents | Nucleotide excision repair (NER) | [105] |
2 | Flap endonucleases (FENs) | Cisplatin | Nucleotide excision repair (NER) and Base excision repair (BER) | [106] |
3 | Chk2 | Paclitaxel | DNA damage checkpoint | [107] |
4 | ATM signaling | Sorafenib | DNA damage checkpoint | [108] |
5 | Apurinic/apyrimidinic endonuclease (APE1) | Irradiation | Base excision repair (BER) | [109] |
Impairment of the apoptotic machinery and associated chemoresistance in HCC
Activation of cell survival signaling and evasion of chemoresistance in HCC
S. No. | Altered signaling pathways | Relevant molecule | Alteration | Targeted therapies | References |
---|---|---|---|---|---|
1 | Hedgehog | SMO | Activating overexpression | GDC-0449, cyclopomine | 2006 [110] |
7 | Hippo | MST1/2 | Down-regulated | – | 2009 [111] |
8 | Hippo | pYAP | Down-regulated | – | 2009 [111] |
3 | Notch | NOTCH1 | Overexpression | Gamma secretase | 2009 [112] |
2 | Wnt/beta-catenin | APC | Inactivating mutation | – | 2012 [113] |
6 | PI3K/AKT/mTOR | MTORC1 | Up-regulated | Everolimus, rapamycin | 2012 [114] |
Autophagy as defense to chemotherapeutic stress
Cancer stem cells in HCC chemoresistance
Evidences for epigenetic regulation of chemoresistance in HCC
S. No. | MiRNAs deregulated in HCC | Mechanism | Expression Level | Reference |
---|---|---|---|---|
1 | miR-21 | Potential biomarker for early stage HCC diagnosis | Up-regulated | [115] |
2 | miR-338-3p | Suppresses HCC cell invasion by inhibiting metalloproteinase (MMP-9) | Down-regulated | [116] |
3 | miR-122 | Inhibits cycle cyclins & reduces MDR expression | Down-regulated | [117] |
4 | miR-181& let-7 | IL-6 and twist-regulated miRNA expression | Up-regulated | [118] |
5 | miR-193a-3p | Affects DNA methylation state | Up-regulated | [119] |
6 | miR-199a/b-3p | Targets mTOR and c-met | Down-regulated | [120] |
7 | miR-210 | Targets apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) in hypoxic HCC | Down-regulated | [121] |
8 | miR-494 | Reduces the expression of PTEN but increases PI3 K and p-Akt expression | Up-regulated | [122] |
9 | miR-1180 | Activates NF-κB pathway by downregulating its negative regulators | Up-regulated | [123] |
10 | miR-122 | Up-regulates IGF-1R that contribute to activation of RAS/RAF/ERK signaling which is associated with drug resistance | Down-regulated | [124] |
Ribosome biogenesis as HCC resistance mechanism
Role of telomerase in HCC chemoresistance
Topoisomerases and HCC chemoresistance
Altered lipid metabolism
Tumor microenvironment
S. No. | Cellular and non cellular components | Role in tumor microenvironment | Effect of various components | References |
---|---|---|---|---|
1 | Tumor associated macrophages (TAMs) | Tumor development by impairing cytotoxic CD8+ T cell mediated immune responses | Chemo resistance in HCC. | [125] |
2 | Cancer associated fibroblasts (CAFs) | Produces growth factors like hepatocyte growth factor (HGF), members of the epidermal growth factor (EGF), fibroblast growth factor (FGF) and members of Wnt families, and cytokines, such as stromal-derived factor (SDF)-1α and IL-6 | Chemo resistance in HCC | |
3 | Matrix metalloproteinases (MMPs) | Causes tissue remodeling, inflammation, tumor cell growth and metastasis in many cancers. MMP-2,-9, and -14 activate TGF-β1, which reciprocally activates MMP. Upregulation of MMP-9 is connected with provocation of PI3 K/PTEN/AKT/mTOR pathways in human HCCs. MMPs also inhibit apoptosis signaling in cancer cells | Chemo resistance in HCC | |
4 | Immune cells | CD8+ T cells, NK cells are fooled by cancer cells as an immune evasion mechanism | Poor prognosis in HCC patients | |
5 | Kupffer cells | Upon activation secrete excessive level of osteopontin | Chemo resistance of cisplatin in small cell lung cancer. It can be postulated to play a role in Hepatocellular carcinoma too | [132] |
6 | Hepatic stellate cells (HSCs) | Produce collagen in the liver. They get activated upon liver damage and undergo phenotypic changes leading liver fibrosis. They secrete hepatocyte growth factor | Chemo resistance in HCC | [133] |
S. No. | Drug | Molecular targets | Phases of clinical trial | Year and references |
---|---|---|---|---|
1 | Sibrotuzumab | FAPs | I | 2003 [134] |
2 | PI-88 | HPR | II | 2009 [135] |
3 | Selumetinib | MEK | II | 2011 [136] |
4 | Brivanib | VEGFR, PDGFR | III | 2013 [137] |
5 | Lilifanib | VEGFR | III | 2013 [138] |
6 | Axitinib | VEGFR | II | 2015 [139] |
7 | Galuniserib | TGF-β | I | 2015 [140] |
Targeted therapy against HCC
S. No. | Drug | Molecular targets | Phases of clinical trial | Year and references |
---|---|---|---|---|
1 | Tremelimumab | CTLA-4 | II | 2013 [141] |
2 | Icaritin | IL-6/Jak2/Stat3 | II | 2015 [142] |
3 | Lenalidomide | TNF-α, interferon γ, IL-6, IL-10, and IL-12. | II | 2015 [143] |
4 | Codrituzumab | Glypican-3 | II | 2016 [144] |
5 | Nivolumab | PD-1 | I | 2016 [145] |
6 | Ipilimumab | CTLA-4 | II | 2017 [146] |
7 | Tasquinimod | Protein S100A9 | II | 2017 [147] |
S. No. | Antigen | Gene transfer vehicle | Phases of clinical trial | Year (Clinicaltrials.gov identifier or reference) |
---|---|---|---|---|
1 | Epidermal growth factor receptor | Lentivirus | I/II | 2013 [148] |
2 | Mucin-1 | – | I/II | 2015 (NCT02587689) |
3 | CD133 | Retrovirus | I | 2015 (NCT02541370) |
4 | Carcinoembryonic antigen | Retrovirus | Preclinical | 2016 [149] |
5 | Epithelial cell adhesion molecule | – | I/II | 2016 (NCT02729493) |
6 | Glypican-3 | – | I/II | 2016 (NCT02723942) |