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Current Drug Targets

Author(s): Maria Manuela Estevinho*, Carlos Fernandes, João Carlos Silva, Ana Catarina Gomes, Edgar Afecto, João Correia and João Carvalho

DOI: 10.2174/1389450122666210412125018

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Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: An Overview

Page: [21 - 32] Pages: 12

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Abstract

Background: Molecular therapy with sorafenib remains the mainstay for advancedstage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate.

Objective: To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma.

Methods: Three online databases (PubMed, Web of Science, and Scopus) were searched, from inception to October 2020. Study selection, analysis, and data collection were independently performed by two authors.

Results: The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance by increasing absorption and intracellular concentration.

Conclusion: A deeper understanding of ABC transporters’ mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.

Keywords: Sorafenib, hepatocellular carcinoma, drug resistance, ABC transporters, p-glycoprotein, efflux pumps.

Graphical Abstract

[1]
Jiang Y, Sun A, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 2019; 567(7747): 257-61.
[http://dx.doi.org/10.1038/s41586-019-0987-8] [PMID: 30814741]
[2]
Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology 2019; 156(2): 477-491.e1.
[http://dx.doi.org/10.1053/j.gastro.2018.08.065] [PMID: 30367835]
[3]
Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity. Cancers (Basel) 2020; 12(6): E1576.
[http://dx.doi.org/10.3390/cancers12061576] [PMID: 32549224]
[4]
Cheng Z, Wei-Qi J, Jin D. New insights on sorafenib resistance in liver cancer with correlation of individualized therapy. Biochim Biophys Acta Rev Cancer 2020; 1874(1): 188382.
[http://dx.doi.org/10.1016/j.bbcan.2020.188382] [PMID: 32522600]
[5]
Nair B, Anto RJ, M S, Nath LR. Kaempferol-mediated sensitization enhances chemotherapeutic efficacy of sorafenib against hepatocellular carcinoma: an in silico and in vitro approach. Adv Pharm Bull 2020; 10(3): 472-6.
[http://dx.doi.org/10.34172/apb.2020.058] [PMID: 32665908]
[6]
Liu Z, Lin Y, Zhang J, et al. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38(1): 447.
[http://dx.doi.org/10.1186/s13046-019-1412-8] [PMID: 31684985]
[7]
Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5(1): 87.
[http://dx.doi.org/10.1038/s41392-020-0187-x] [PMID: 32532960]
[8]
Xia S, Pan Y, Liang Y, Xu J, Cai X. The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. EBioMedicine 2020; 51: 102610.
[http://dx.doi.org/10.1016/j.ebiom.2019.102610] [PMID: 31918403]
[9]
Bins S, van Doorn L, Phelps MA, et al. Influence of OATP1B1 function on the disposition of sorafenib-β-D-glucuronide. Clin Transl Sci 2017; 10(4): 271-9.
[http://dx.doi.org/10.1111/cts.12458] [PMID: 28371445]
[10]
Al-Abdulla R, Lozano E, Macias RIR, et al. Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib. Br J Pharmacol 2019; 176(6): 787-800.
[http://dx.doi.org/10.1111/bph.14563] [PMID: 30592786]
[11]
Chen M, Neul C, Schaeffeler E, et al. Sorafenib activity and disposition in liver cancer does not depend on organic cation transporter 1. Clin Pharmacol Ther 2020; 107(1): 227-37.
[http://dx.doi.org/10.1002/cpt.1588] [PMID: 31350763]
[12]
Li J, Yang Z, Tuo B. Role of OCT1 in hepatocellular carcinoma. OncoTargets Ther 2019; 12: 6013-22.
[http://dx.doi.org/10.2147/OTT.S212088] [PMID: 31413596]
[13]
Marin JJG, Macias RIR, Monte MJ, et al. Molecular bases of drug resistance in hepatocellular carcinoma. Cancers (Basel) 2020; 12(6): 1663.
[http://dx.doi.org/10.3390/cancers12061663] [PMID: 32585893]
[14]
Miners JO, Chau N, Rowland A, et al. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia. Biochem Pharmacol 2017; 129: 85-95.
[http://dx.doi.org/10.1016/j.bcp.2017.01.002] [PMID: 28065859]
[15]
Vasilyeva A, Durmus S, Li L, et al. Hepatocellular shuttling and recirculation of sorafenib-glucuronide is dependent on abcc2, abcc3, and oatp1a/1b. Cancer Res 2015; 75(13): 2729-36.
[16]
Gong L, Giacomini MM, Giacomini C, Maitland ML, Altman RB, Klein TE. PharmGKB summary: sorafenib pathways. Pharmacogenet Genomics 2017; 27(6): 240-6.
[http://dx.doi.org/10.1097/FPC.0000000000000279] [PMID: 28362716]
[17]
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378-90.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[18]
Cheng A-L, Kang Y-K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10(1): 25-34.
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[19]
Marrero JA, Kudo M, Venook AP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 2016; 65(6): 1140-7.
[http://dx.doi.org/10.1016/j.jhep.2016.07.020] [PMID: 27469901]
[20]
Ganten TM, Stauber RE, Schott E, et al. Sorafenib in patients with hepatocellular carcinoma-results of the observational insight study. Clin Cancer Res 2017; 23(19): 5720-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0919] [PMID: 28698202]
[21]
Mehendale-Munj S. Breast cancer resistance protein: a potential therapeutic target for cancer. Curr Drug Targets 2020.
[http://dx.doi.org/10.2174/1389450121999201125200132] [PMID: 33243119]
[22]
Liu X. Overview: role of drug transporters in drug disposition and its clinical significance. Adv Exp Med Biol 2019; 1141: 1-12.
[http://dx.doi.org/10.1007/978-981-13-7647-4_1] [PMID: 31571163]
[23]
Xiao Q, Zhou Y, Lauschke VM. Ethnogeographic and inter-individual variability of human ABC transporters. Hum Genet 2020; 139(5): 623-46.
[http://dx.doi.org/10.1007/s00439-020-02150-6] [PMID: 32206879]
[24]
Marquez B, Van Bambeke F. ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions. Curr Drug Targets 2011; 12(5): 600-20.
[http://dx.doi.org/10.2174/138945011795378504] [PMID: 21039335]
[25]
Pasello M, Giudice AM, Scotlandi K. The ABC subfamily A transporters: Multifaceted players with incipient potentialities in cancer. Semin Cancer Biol 2020; 60: 57-71.
[http://dx.doi.org/10.1016/j.semcancer.2019.10.004] [PMID: 31605751]
[26]
Domenichini A, Adamska A, Falasca M. ABC transporters as cancer drivers: Potential functions in cancer development. Biochim Biophys Acta, Gen Subj 2019; 1863(1): 52-60.
[http://dx.doi.org/10.1016/j.bbagen.2018.09.019] [PMID: 30268729]
[27]
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018; 18(7): 452-64.
[http://dx.doi.org/10.1038/s41568-018-0005-8] [PMID: 29643473]
[28]
Cui H, Zhang AJ, Chen M, Liu JJ. ABC Transporter inhibitors in reversing multidrug resistance to chemotherapy. Curr Drug Targets 2015; 16(12): 1356-71.
[http://dx.doi.org/10.2174/1389450116666150330113506] [PMID: 25901528]
[29]
Ceballos MP, Rigalli JP, Ceré LI, Semeniuk M, Catania VA, Ruiz ML. ABC transporters: regulation and association with multidrug resistance in hepatocellular carcinoma and colorectal carcinoma. Curr Med Chem 2019; 26(7): 1224-50.
[http://dx.doi.org/10.2174/0929867325666180105103637] [PMID: 29303075]
[30]
Yang X-R, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010; 59(7): 953-62.
[http://dx.doi.org/10.1136/gut.2008.176271] [PMID: 20442200]
[31]
Wei L, Huang N, Yang L, et al. Sorafenib reverses multidrug resistance of hepatoma cells in vitro. Nan Fang Yi Ke Da Xue Xue Bao 2009; 29(5): 1016-1019, 1023.
[PMID: 19460734]
[32]
Hoffmann K, Franz C, Xiao Z, et al. Sorafenib modulates the gene expression of multi-drug resistance mediating ATP-binding cassette proteins in experimental hepatocellular carcinoma. Anticancer Res 2010; 30(11): 4503-8.
[PMID: 21115899]
[33]
Arrondeau J, Mir O, Boudou-Rouquette P, et al. Sorafenib exposure decreases over time in patients with hepatocellular carcinoma. Invest New Drugs 2012; 30(5): 2046-9.
[http://dx.doi.org/10.1007/s10637-011-9764-8] [PMID: 22038662]
[34]
Ye C-G, Yeung JH-K, Huang G-L, et al. Increased glutathione and mitogen-activated protein kinase phosphorylation are involved in the induction of doxorubicin resistance in hepatocellular carcinoma cells. Hepatol Res 2013; 43(3): 289-99.
[http://dx.doi.org/10.1111/j.1872-034X.2012.01067.x] [PMID: 22882382]
[35]
Chow AK-M, Ng L, Lam CS-C, et al. The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One 2013; 8(11): e78675-5.
[http://dx.doi.org/10.1371/journal.pone.0078675] [PMID: 24244338]
[36]
Huang W-C, Hsieh Y-L, Hung C-M, et al. BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One 2013; 8(12): e83627.
[http://dx.doi.org/10.1371/journal.pone.0083627] [PMID: 24391798]
[37]
Liang Y, Zheng T, Song R, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology 2013; 57(5): 1847-57.
[http://dx.doi.org/10.1002/hep.26224] [PMID: 23299930]
[38]
Colombo F, Trombetta E, Cetrangolo P, et al. Giant lysosomes as a chemotherapy resistance mechanism in hepatocellular carcinoma cells. PLoS One 2014; 9(12): e114787.
[http://dx.doi.org/10.1371/journal.pone.0114787] [PMID: 25493932]
[39]
Kim JB, Lee M, Park SY, et al. Sorafenib inhibits cancer side population cells by targeting c-Jun N-terminal kinase signaling. Mol Med Rep 2015; 12(6): 8247-52.
[http://dx.doi.org/10.3892/mmr.2015.4422] [PMID: 26460271]
[40]
Li M, Zhang L, Ge C, et al. An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma. Oncotarget 2015; 6(28): 25149-60.
[http://dx.doi.org/10.18632/oncotarget.4438] [PMID: 26327240]
[41]
Wang H, Qian Z, Zhao H, et al. CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells. Mol Med Rep 2015; 12(3): 3902-8.
[http://dx.doi.org/10.3892/mmr.2015.3871] [PMID: 26035694]
[42]
Rigalli JP, Ciriaci N, Arias A, et al. Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity. PLoS One 2015; 10(3): e0119502.
[http://dx.doi.org/10.1371/journal.pone.0119502] [PMID: 25781341]
[43]
Zhou J-N, Zeng Q, Wang H-Y, et al. MicroRNA-125b attenuates epithelial-mesenchymal transitions and targets stem-like liver cancer cells through small mothers against decapentaplegic 2 and 4. Hepatology 2015; 62(3): 801-15.
[http://dx.doi.org/10.1002/hep.27887] [PMID: 25953743]
[44]
Wu C-H, Wu X, Zhang H-W. Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor. J Surg Res 2016; 206(2): 371-9.
[http://dx.doi.org/10.1016/j.jss.2016.08.014] [PMID: 27884331]
[45]
Fouquet G, Debuysscher V, Ouled-Haddou H, et al. Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs. Oncotarget 2016; 7(22): 32493-503.
[http://dx.doi.org/10.18632/oncotarget.8679] [PMID: 27081035]
[46]
Tomonari T, Takeishi S, Taniguchi T, et al. MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma. Oncotarget 2016; 7(6): 7207-15.
[http://dx.doi.org/10.18632/oncotarget.6889] [PMID: 26769852]
[47]
Wang J, Lian Y, Gu Y, et al. Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells. Oncotarget 2017; 8(62): 105047-60.
[http://dx.doi.org/10.18632/oncotarget.22086] [PMID: 29285232]
[48]
Dong J, Zhai B, Sun W, Hu F, Cheng H, Xu J. Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells. PLoS One 2017; 12(9): e0185088.
[http://dx.doi.org/10.1371/journal.pone.0185088] [PMID: 28934275]
[49]
Ding J, Zhou X-T, Zou H-Y, Wu J. Hedgehog signaling pathway affects the sensitivity of hepatoma cells to drug therapy through the ABCC1 transporter. Lab Invest 2017; 97(7): 819-32.
[http://dx.doi.org/10.1038/labinvest.2017.34] [PMID: 28414325]
[50]
Tandia M, Mhiri A, Paule B, et al. Correlation between clinical response to sorafenib in hepatocellular carcinoma treatment and polymorphisms of P-glycoprotein (ABCB1) and of breast cancer resistance protein (ABCG2): monocentric study. Cancer Chemother Pharmacol 2017; 79(4): 759-66.
[http://dx.doi.org/10.1007/s00280-017-3268-y] [PMID: 28289864]
[51]
Yang X, Xia W, Chen L, et al. Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma. Oncotarget 2018; 9(79): 34996-5007.
[http://dx.doi.org/10.18632/oncotarget.26209] [PMID: 30405889]
[52]
Bhagyaraj E, Ahuja N, Kumar S, et al. TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR. Cell Cycle 2019; 18(24): 3589-602.
[http://dx.doi.org/10.1080/15384101.2019.1693120] [PMID: 31739702]
[53]
Di Giacomo S, Briz O, Monte MJ, et al. Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps. Arch Toxicol 2019; 93(3): 623-34.
[http://dx.doi.org/10.1007/s00204-019-02395-9] [PMID: 30659321]
[54]
Chouhan S, Singh S, Athavale D, et al. Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucosedependent alterations in reactive oxygen species, P-glycoprotein and DKK4. J Biosci 2020; 45: 45.
[http://dx.doi.org/10.1007/s12038-020-00065-y] [PMID: 32713860]
[55]
Wang M, Wang Z, Zhi X, et al. SOX9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma. Biomed Pharmacother 2020; 129: 110315.
[http://dx.doi.org/10.1016/j.biopha.2020.110315] [PMID: 32554246]
[56]
Makol A, Kaur H, Sharma S, Kanthaje S, Kaur R, Chakraborti A. Vimentin as a potential therapeutic target in sorafenib resistant HepG2, a HCC model cell line. Clin Mol Hepatol 2020; 26(1): 45-53.
[57]
Shao W, Zhu W, Lin J, et al. Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR. Neoplasia 2020; 22(1): 1-9.
[http://dx.doi.org/10.1016/j.neo.2019.08.002] [PMID: 31751859]
[58]
Fan G, Wei X, Xu X. Is the era of sorafenib over? A review of the literature. Ther Adv Med Oncol 2020; 12: 1758835920927602.
[http://dx.doi.org/10.1177/1758835920927602] [PMID: 32518599]
[59]
Espelt MV, Bacigalupo ML, Carabias P, Troncoso MF. MicroRNAs contribute to ATP-binding cassette transporter- and autophagy-mediated chemoresistance in hepatocellular carcinoma. World J Hepatol 2019; 11(4): 344-58.
[http://dx.doi.org/10.4254/wjh.v11.i4.344] [PMID: 31114639]
[60]
Thomas S, Prasanna Thankappan A, Devi Padma U, Keechilat P. Therapeutic drug monitoring of sorafenib in hepatocellular carcinoma patients. Ther Drug Monit 2020; 42(2): 345-7.
[http://dx.doi.org/10.1097/FTD.0000000000000723] [PMID: 31913863]
[61]
Belisario DC, Akman M, Godel M, et al. ABCA1/ABCB1 ratio determines chemo- and immune-sensitivity in human osteosarcoma. Cells 2020; 9(3): 647.
[http://dx.doi.org/10.3390/cells9030647] [PMID: 32155954]
[62]
Chew SA, Moscato S, George S, Azimi B, Danti S. Liver cancer: current and future trends using biomaterials. Cancers (Basel) 2019; 11(12): E2026.
[http://dx.doi.org/10.3390/cancers11122026] [PMID: 31888198]
[63]
Gupta SK, Singh P, Ali V, Verma M. Role of membrane-embedded drug efflux ABC transporters in the cancer chemotherapy. Oncol Rev 2020; 14(2): 448.
[http://dx.doi.org/10.4081/oncol.2020.448] [PMID: 32676170]
[64]
Cai H, Yang Y, Peng F, Liu Y, Fu X, Ji B. Gold nanoparticles-loaded anti-miR221 enhances antitumor effect of sorafenib in hepatocellular carcinoma cells. Int J Med Sci 2019; 16(12): 1541-8.
[http://dx.doi.org/10.7150/ijms.37427] [PMID: 31839741]
[65]
Soldevilla MM, Villanueva H, Casares N, et al. MRP1-CD28 bi-specific oligonucleotide aptamers: target costimulation to drug-resistant melanoma cancer stem cells. Oncotarget 2016; 7(17): 23182-96.
[http://dx.doi.org/10.18632/oncotarget.8095] [PMID: 26992239]