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Review

Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma

ORCID Icon, , &
Pages 985-1006 | Received 24 Dec 2020, Accepted 09 Jul 2021, Published online: 22 Jul 2021

References

  • Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557–588.
  • Ghouri YA, Mian I, Blechacz B. Cancer review: cholangiocarcinoma. J Carcinog. 2015;14:1.
  • Roy S, Glaser S, Chakraborty S. Inflammation and progression of cholangiocarcinoma: role of angiogenic and lymphangiogenic mechanisms. Front Med (Lausanne). 2019;6:293.
  • Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: epidemiology and risk factors. Liver Int. 2019;39(Suppl 1):19–31.
  • Yongvanit P, Pinlaor S, Bartsch H. Oxidative and nitrative DNA damage: key events in opisthorchiasis-induced carcinogenesis. Parasitol Int. 2012;61:130–135.
  • Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v28–v37.
  • Luvira V, Nilprapha K, Bhudhisawasdi V, et al. Cholangiocarcinoma patient outcome in Northeastern Thailand: single-center prospective study. Asian Pac J Cancer Prev. 2016;17:401–406.
  • Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 2012;61:1657–1669.
  • Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383:2168–2179.
  • Jung CFM, Lavole J, Barret M, et al. Local therapy in advanced cholangiocarcinoma: a review of current endoscopic, medical, and oncologic treatment options. Oncology 2019;97:191–201.
  • Wirasorn K, Ngamprasertchai T, Khuntikeo N, et al. Adjuvant chemotherapy in resectable cholangiocarcinoma patients. J Gastroenterol Hepatol. 2013;28:1885–1891.
  • Rangarajan K, Simmons G, Manas D, et al. Systemic adjuvant chemotherapy for cholangiocarcinoma surgery: a systematic review and meta-analysis. Eur J Surg Oncol. 2020;46:684–693.
  • Dabney RS, Khalife M, Shahid K, et al. Molecular pathways and targeted therapy in cholangiocarcinoma. Clin Adv Hematol Oncol. 2019;17:630–637.
  • Lamarca A, Barriuso J, McNamara MG, et al. Molecular targeted therapies: ready for “prime time” in biliary tract cancer. J Hepatol. 2020;73:170–185.
  • Massironi S, Pilla L, Elvevi A, et al. New and emerging systemic therapeutic options for advanced cholangiocarcinoma. Cells. 2020;9.
  • Simile MM, Bagella P, Vidili G, et al. Targeted therapies in cholangiocarcinoma: emerging evidence from clinical trials. Medicina (Kaunas). 2019;55.
  • Titapun A, Pugkhem A, Luvira V, et al. Outcome of curative resection for perihilar cholangiocarcinoma in Northeast Thailand. World J Gastrointest Oncol. 2015;7:503–512.
  • Hyder O, Hatzaras I, Sotiropoulos GC, et al. Recurrence after operative management of intrahepatic cholangiocarcinoma. Surgery. 2013;153:811–818.
  • Yamamoto M, Takasaki K, Otsubo T, et al. Recurrence after surgical resection of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2001;8:154–157.
  • Al Ustwani O, Iancu D, Yacoub R, et al. Detection of circulating tumor cells in cancers of biliary origin. J Gastrointest Oncol. 2012;3:97–104.
  • Gil E, Joh JW, Park HC, et al. Predictors and patterns of recurrence after curative liver resection in intrahepatic cholangiocarcinoma, for application of postoperative radiotherapy: a retrospective study. World J Surg Oncol. 2015;13:227.
  • Tabrizian P, Jibara G, Hechtman JF, et al. Outcomes following resection of intrahepatic cholangiocarcinoma. HPB. 2015;17:344–351.
  • Groot Koerkamp B, Wiggers JK, Allen PJ, et al. Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection. J Am Coll Surg. 2015;221:1041–1049.
  • Mao ZY, Guo XC, Su D, et al. Prognostic factors of cholangiocarcinoma after surgical resection: a retrospective study of 293 patients. Med Sci Monit. 2015;21:2375–2381.
  • Luvira V, Eurboonyanun C, Bhudhisawasdi V, et al. Patterns of recurrence after resection of mass-forming type intrahepatic cholangiocarcinomas. Asian Pac J Cancer Prev. 2016;17:4735–4739.
  • Komaya K, Ebata T, Shirai K, et al. Recurrence after resection with curative intent for distal cholangiocarcinoma. Br J Surg. 2017;104:426–433.
  • Zhang XF, Beal EW, Bagante F, et al. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg. 2018;105:848–856.
  • Zhang XF, Beal EW, Chakedis J, et al. Defining early recurrence of hilar cholangiocarcinoma after curative-intent surgery: a multi-institutional study from the US extrahepatic biliary malignancy consortium. World J Surg. 2018;42:2919–2929.
  • Ohira M, Kobayashi T, Hashimoto M, et al. Prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative resection: a retrospective cohort study. Int J Surg. 2018;54:156–162.
  • Blaga MM, Brasoveanu V, Stroescu C, et al. Pattern of the first recurrence has no impact on long-term survival after curative intent surgery for perihilar cholangiocarcinomas. Gastroenterol Res Pract. 2018;2018:2546257.
  • Choi HS, Kang KM, Jeong BK, et al. Patterns of failure after resection of extrahepatic bile duct cancer: implications for adjuvant radiotherapy indication and treatment volumes. Radiat Oncol. 2018;13:85.
  • Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004;15:1339–1343.
  • Gebbia V, Giuliani F, Maiello E, et al. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001;19:4089–4091.
  • Bhudhisawasdi V, Talabnin C, Pugkhem A, et al. Evaluation of postoperative adjuvant chemotherapy for intrahepatic cholangiocarcinoma patients undergoing R1 and R2 resections. Asian Pac J Cancer Prev. 2012;13:169–174.
  • Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27:23–44.
  • Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105:192–202.
  • Edeline J, Benabdelghani M, Bertaut A, et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019;37:658–667.
  • Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663–673.
  • Morris TP, Kahan BC, White IR. Choosing sensitivity analyses for randomised trials: principles. BMC Med Res Methodol. 2014;14:11.
  • Porta M. Comments regarding the positive review of “A Dictionary of Epidemiology.” Ann Epidemiol. 2015;25:303.
  • Thabane L, Mbuagbaw L, Zhang S, et al. A tutorial on sensitivity analyses in clinical trials: the what, why, when and how. BMC Med Res Methodol. 2013;13:92.
  • de Souza RJ, Eisen RB, Perera S, et al. Best (but oft-forgotten) practices: sensitivity analyses in randomized controlled trials. Am J Clin Nutr. 2016;103:5–17.
  • Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019;37:1015–1027.
  • Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281.
  • Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5:824–830.
  • Lamarca A, Hubner RA, David Ryder W, et al. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25:2328–2338.
  • DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245:755–762.
  • Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma. Lancet. 2005;366:1303–1314.
  • Khan SA, Taylor-Robinson SD, Toledano MB, et al. Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol. 2002;37:806–813.
  • Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143:88–98e83; quiz e14.
  • Chan-On W, Nairismagi ML, Ong CK, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–1478.
  • Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet. 2012;44:690–693.
  • Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 2017;7:1116–1135.
  • Jusakul A, Loilome W, Namwat N, et al. Liver fluke-induced hepatic oxysterols stimulate DNA damage and apoptosis in cultured human cholangiocytes. Mutat Res. 2012;731:48–57.
  • Jusakul A, Yongvanit P, Loilome W, et al. Mechanisms of oxysterol-induced carcinogenesis. Lipids Health Dis. 2011;10:44.
  • Thanan R, Murata M, Pinlaor S, et al. Urinary 8-oxo-7,8-dihydro-2ʹ-deoxyguanosine in patients with parasite infection and effect of antiparasitic drug in relation to cholangiocarcinogenesis. Cancer Epidemiol Biomarkers Prev. 2008;17:518–524.
  • Thanan R, Oikawa S, Yongvanit P, et al. Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma. Free Radic Biol Med. 2012;52:1465–1472.
  • Loilome W, Yongvanit P, Wongkham C, et al. Altered gene expression in Opisthorchis viverrini-associated cholangiocarcinoma in hamster model. Mol Carcinog. 2006;45:279–287.
  • Loilome W, Yooyuen S, Namwat N, et al. PRKAR1A overexpression is associated with increased ECPKA autoantibody in liver fluke-associated cholangiocarcinoma: application for assessment of the risk group. Tumour Biol. 2012;33:2289–2298.
  • Techasen A, Loilome W, Namwat N, et al. Myristoylated alanine-rich C kinase substrate phosphorylation promotes cholangiocarcinoma cell migration and metastasis via the protein kinase C-dependent pathway. Cancer Sci. 2010;101:658–665.
  • Dokduang H, Juntana S, Techasen A, et al. Survey of activated kinase proteins reveals potential targets for cholangiocarcinoma treatment. Tumour Biol. 2013;34:3519–3528.
  • Loilome W, Juntana S, Namwat N, et al. PRKAR1A is overexpressed and represents a possible therapeutic target in human cholangiocarcinoma. Int J Cancer. 2010;129:34–44.
  • Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65:1566–1584.
  • Padthaisong S, Thanee M, Techasen A, et al. Nimotuzumab inhibits cholangiocarcinoma cell metastasis via suppression of the epithelial-mesenchymal transition process. Anticancer Res. 2017;37:3591–3597.
  • Padthaisong S, Thanee M, Namwat N, et al. A panel of protein kinase high expression is associated with postoperative recurrence in cholangiocarcinoma. BMC Cancer. 2020;20:154.
  • Dokduang H, Jamnongkarn W, Promraksa B, et al. In vitro and in vivo anti-tumor effects of pan-HER inhibitor varlitinib on cholangiocarcinoma cell lines. Drug Des Devel Ther. 2020;14:2319–2334.
  • Boonjaraspinyo S, Boonmars T, Wu Z, et al. Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma. Tumour Biol. 2012;33:1785–1802.
  • Boonjaraspinyo S, Wu Z, Boonmars T, et al. Overexpression of PDGFA and its receptor during carcinogenesis of Opisthorchis viverrini-associated cholangiocarcinoma. Parasitol Int. 2012;61:145–150.
  • Johnson SM, Gulhati P, Rampy BA, et al. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010;210(767–776):776.
  • McDowell KA, Riggins GJ, Gallia GL. Targeting the AKT pathway in glioblastoma. Curr Pharm Des. 2011;17:2411–2420.
  • Yothaisong S, Dokduang H, Techasen A, et al. Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy. Tumour Biol. 2013;34:3637–3648.
  • Yothaisong S, Thanee M, Namwat N, et al. Opisthorchis viverrini infection activates the PI3K/ AKT/PTEN and Wnt/beta-catenin signaling pathways in a Cholangiocarcinogenesis model. Asian Pac J Cancer Prev. 2014;15:10463–10468.
  • Padthaisong S, Dokduang H, Yothaisong S, et al. Inhibitory effect of NVP-BKM120 on cholangiocarcinoma cell growth. Oncol Lett. 2018;16:1627–1633.
  • Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–1229.
  • Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.
  • Pinlaor S, Prakobwong S, Hiraku Y, et al. Reduction of periductal fibrosis in liver fluke-infected hamsters after long-term curcumin treatment. Eur J Pharmacol. 2010;638:134–141.
  • Pinlaor S, Yongvanit P, Prakobwong S, et al. Curcumin reduces oxidative and nitrative DNA damage through balancing of oxidant-antioxidant status in hamsters infected with Opisthorchis viverrini. Mol Nutr Food Res. 2009;53:1316–1328.
  • Prakobwong S, Gupta SC, Kim JH, et al. Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis. 2011;32:1372–1380.
  • Prakobwong S, Khoontawad J, Yongvanit P, et al. Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis. Int J Cancer. 2011;129:88–100.
  • Suphim B, Prawan A, Kukongviriyapan U, et al. Redox modulation and human bile duct cancer inhibition by curcumin. Food Chem Toxicol. 2010;48:2265–2272.
  • Khoontawad J, Wongkham C, Hiraku Y, et al. Proteomic identification of peroxiredoxin 6 for host defence against Opisthorchis viverrini infection. Parasite Immunol. 2010;32:314–323.
  • San TT, Khaenam P, Prachayasittikul V, et al. Curcumin enhances chemotherapeutic effects and suppresses ANGPTL4 in anoikis-resistant cholangiocarcinoma cells. Heliyon. 2020;6:e03255.
  • Boonjaraspinyo S, Boonmars T, Aromdee C, et al. Indirect effect of a turmeric diet: enhanced bile duct proliferation in Syrian hamsters with a combination of partial obstruction by Opisthorchis viverrini infection and inflammation by N-nitrosodimethylamine administration. Parasitol Res. 2011;108:7–14.
  • Boonjaraspinyo S, Boonmars T, Aromdee C, et al. Turmeric reduces inflammatory cells in hamster opisthorchiasis. Parasitol Res. 2009;105:1459–1463.
  • Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry. 2004;65:1317–1330.
  • Albini A, Dell’Eva R, Vene R, et al. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets. Faseb J. 2006;20:527–529.
  • Gerhauser C. Beer constituents as potential cancer chemopreventive agents. Eur J Cancer. 2005;41:1941–1954.
  • Gerhauser C, Alt A, Heiss E, et al. Cancer chemopreventive activity of Xanthohumol, a natural product derived from hop. Mol Cancer Ther. 2002;1:959–969.
  • Dokduang H, Yongvanit P, Namwat N, et al. Xanthohumol inhibits STAT3 activation pathway leading to growth suppression and apoptosis induction in human cholangiocarcinoma cells. Oncol Rep. 2016;35:2065–2072.
  • Jamnongkan W, Thanee M, Yongvanit P, et al. Antifibrotic effect of xanthohumol in combination with praziquantel is associated with altered redox status and reduced iron accumulation during liver fluke-associated cholangiocarcinogenesis. PeerJ. 2018;6:e4281.
  • Thongchot S, Thanee M, Loilome W, et al. Curative effect of xanthohumol supplementation during liver fluke-associated cholangiocarcinogenesis: potential involvement of autophagy. J Tradit Complement Med. 2020;10:230–235.
  • Bradley R, Langley BO, Ryan JJ, et al. Xanthohumol microbiome and signature in healthy adults (the XMaS trial): a phase I triple-masked, placebo-controlled clinical trial. Trials. 2020;21:835.
  • Murtaza GLU, Najam-Ul-Haq M, Sajjad A, et al. Resveratrol: an active natural compound in red wines for health. J Food Drug Anal. 2013;21:1–12.
  • Lettieri Barbato D, Tatulli G, Aquilano K, et al. Inhibition of age-related cytokines production by ATGL: a mechanism linked to the anti-inflammatory effect of resveratrol. Mediators Inflamm. 2014;2014:917698.
  • Roncoroni L, Elli L, Dolfini E, et al. Resveratrol inhibits cell growth in a human cholangiocarcinoma cell line. Liver Int. 2008;28:1426–1436.
  • Frampton GA, Lazcano EA, Li H, et al. Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents. Lab Invest. 2010;90:1325–1338.
  • Thongchot S, Ferraresi A, Vidoni C, et al. Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells. Cancer Lett. 2018;430:160–171.
  • Ahn K. The worldwide trend of using botanical drugs and strategies for developing global drugs. BMB Rep. 2017;50:111–116.
  • Plengsuriyakarn T, Viyanant V, Eursitthichai V, et al. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models. BMC Complement Altern Med. 2012;12:23.
  • Promraksa B, Phetcharaburanin J, Namwat N, et al. Evaluation of anticancer potential of Thai medicinal herb extracts against cholangiocarcinoma cell lines. PLoS One. 2019;14:e0216721.
  • Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev. 1990;70:43–77.
  • Kaira K, Sunose Y, Ohshima Y, et al. Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer. BMC Cancer. 2013;13:482.
  • Janpipatkul K, Suksen K, Borwornpinyo S, et al. Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration. Cell Signal. 2014;26:1668–1679.
  • Li J, Qiang J, Chen SF, et al. The impact of L-type amino acid transporter 1 (LAT1) in human hepatocellular carcinoma. Tumour Biol. 2013;34:2977–2981.
  • Yanagisawa N, Hana K, Nakada N, et al. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas. Cancer Med. 2014;3:1246–1255.
  • Rosilio C, Nebout M, Imbert V, et al. L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia. Leukemia. 2015;29:1253–1266.
  • Wempe MF, Rice PJ, Lightner JW, et al. Metabolism and pharmacokinetic studies of JPH203, an L-amino acid transporter 1 (LAT1) selective compound. Drug Metab Pharmacokinet. 2012;27:155–161.
  • Yun DW, Lee SA, Park MG, et al. JPH203, an L-type amino acid transporter 1-selective compound, induces apoptosis of YD-38 human oral cancer cells. J Pharmacol Sci. 2014;124:208–217.
  • Yothaisong S, Namwat N, Yongvanit P, et al. Increase in L-type amino acid transporter 1 expression during cholangiocarcinogenesis caused by liver fluke infection and its prognostic significance. Parasitol Int. 2017;66:471–478.
  • Guan J, Lo M, Dockery P, et al. The xc- cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine. Cancer Chemother Pharmacol. 2009;64:463–472.
  • Huang Y, Dai Z, Barbacioru C, et al. Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance. Cancer Res. 2005;65:7446–7454.
  • Ishimoto T, Nagano O, Yae T, et al. CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc− and Thereby Promotes Tumor Growth. Cancer Cell. 2011;19(3):387–400.
  • Kunlabut K, Vaeteewoottacharn K, Wongkham C, et al. Aberrant expression of CD44 in bile duct cancer correlates with poor prognosis. Asian Pac J Cancer Prev. 2012;13 Suppl:95–99.
  • Thanee M, Loilome W, Techasen A, et al. CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: a target for cholangiocarcinoma treatment. Cancer Science. 2016;107(7):991–1000.
  • Du -X-X, Li Y-J, Wu C-L, et al. Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin. Biomed Pharmacothe. 2013;67(5):417–424.
  • Lai H, Singh NP. Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Cancer Lett. 2006;231(1):43–48.
  • Qu C, Ma J, Liu X, et al. Dihydroartemisinin exerts anti-tumor activity by inducing mitochondrion and endoplasmic reticulum apoptosis and autophagic cell death in human glioblastoma cells. Front Cell Neurosci. 2019;97:310.
  • Chen Q, Chen L, Kong D, et al. Dihydroartemisinin alleviates bile duct ligation-induced liver fibrosis and hepatic stellate cell activation by interfering with the PDGF-βR/ERK signaling pathway. Int Immunopharmacol. 2016;34:250–258.
  • Thongchot S, Vidoni C, Ferraresi A, et al. Dihydroartemisinin induces apoptosis and autophagy-dependent cell death in cholangiocarcinoma through a DAPK1-BECLIN1 pathway. Mol Carcinog. 2018;57:1735–1750.
  • Guragain D, Seubwai W, Kobayashi D, et al. Artesunate and chloroquine induce cytotoxic activity on cholangiocarcinoma cells via different cell death mechanisms. Cell Mol Biol. 2018;64:113–118.
  • Hashimoto H, Messerli SM, Sudo T, et al. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3:243–246.
  • Liu Y, Fang S, Sun Q, et al. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016;480:415–421.
  • Sharmeen S, Skrtic M, Sukhai MA, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116:3593–3603.
  • Jiang L, Wang P, Sun YJ, et al. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. J Exp Clin Cancer Res. 2019;38:265.
  • Pouliot JF, L’Heureux F, Liu Z, et al. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem Pharmacol. 1997;53:17–25.
  • Intuyod K, Hahnvajanawong C, Pinlaor P, et al. Anti-parasitic drug ivermectin exhibits potent anticancer activity against gemcitabine-resistant cholangiocarcinoma in vitro. Anticancer Res. 2019;39:4837–4843.
  • Saengboonmee C, Seubwai W, Pairojkul C, et al. High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. Sci Rep. 2016;6:18995.
  • Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer. 2009;16:1103–1123.
  • Belfiore A, Malaguarnera R. Insulin receptor and cancer. Endocr Relat Cancer. 2011;18:R125–147.
  • Garcia-Jimenez C, Garcia-Martinez JM, Chocarro-Calvo A, et al. A new link between diabetes and cancer: enhanced WNT/beta-catenin signaling by high glucose. J Mol Endocrinol. 2014;52:R51–66.
  • Pernicova I, Korbonits M. Metformin--mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–156.
  • Chaiteerakij R, Yang JD, Harmsen WS, et al. Risk factors for intrahepatic cholangiocarcinoma: association between metformin use and reduced cancer risk. Hepatology. 2013;57:648–655.
  • Wandee J, Prawan A, Senggunprai L, et al. Metformin enhances cisplatin induced inhibition of cholangiocarcinoma cells via AMPK-mTOR pathway. Life Sci. 2018;207:172–183.
  • medicine NUSnlf. Metformin United State: cilnicaltrials.gov; 2021 [ cited 30 Apr 2021]. Available from: https://www.clinicaltrials.gov/ct2/results?cond=&term=metformin&cntry=&state=&city=&dist=
  • Saengboonmee C, Seubwai W, Cha’on U, et al. Metformin exerts antiproliferative and anti-metastatic effects against cholangiocarcinoma cells by targeting STAT3 and NF-kB. Anticancer Res. 2017;37:115–123.
  • Molenaar RJ, Coelen RJS, Khurshed M, et al. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open. 2017;7:e014961.
  • Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51–81.
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
  • Baxevanis CN, Perez SA, Papamichail M. Cancer immunotherapy. Crit Rev Clin Lab Sci. 2009;46:167–189.
  • Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125:3335–3337.
  • Piha-Paul SA, Oh DY, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147:2190–2198.
  • Finkelmeier F, Waidmann O, Trojan J. Nivolumab for the treatment of hepatocellular carcinoma. Expert Rev Anticancer Ther. 2018;18:1169–1175.
  • Kim RD, Sanoff HK, Poklepovic AS, et al. A multi-institutional phase 2 trial of regorafenib in refractory advanced biliary tract cancer. Cancer. 2020;126:3464–3470.
  • Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561.
  • Sangkhamanon S, Jongpairat P, Sookprasert A, et al. Programmed death-ligand 1 (PD-L1) expression associated with a high neutrophil/lymphocyte ratio in cholangiocarcinoma. Asian Pac J Cancer Prev. 2017;18:1671–1674.
  • Thepmalee C, Panya A, Junking M, et al. Inhibition of IL-10 and TGF-beta receptors on dendritic cells enhances activation of effector T-cells to kill cholangiocarcinoma cells. Hum Vaccin Immunother. 2018;14:1423–1431.
  • Sawasdee N, Thepmalee C, Sujjitjoon J, et al. Gemcitabine enhances cytotoxic activity of effector T-lymphocytes against chemo-resistant cholangiocarcinoma cells. Int Immunopharmacol. 2020;78:106006.
  • Ma S, Li X, Wang X, et al. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15:2548–2560.
  • Yuan SF, Li KZ, Wang L, et al. Expression of MUC1 and its significance in hepatocellular and cholangiocarcinoma tissue. World J Gastroenterol. 2005;11:4661–4666.
  • Supimon K, Sangsuwannukul T, Sujjitjoon J, et al. Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. Sci Rep. 2021;11:6276.
  • Phanthaphol N, Somboonpatarakun C, Suwanchiwasiri K, et al. Chimeric antigen receptor T cells targeting integrin alphavbeta6 expressed on cholangiocarcinoma cells. Front Oncol. 2021;11:657868.
  • Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81–94.
  • Russo M, Siravegna G, Blaszkowsky LS, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 2016;6:147–153.
  • Bragazzi MC, Ridola L, Safarikia S, et al. New insights into cholangiocarcinoma: multiple stems and related cell lineages of origin. Ann Gastroenterol. 2018;31:42–55.
  • Brandi G, Farioli A, Astolfi A, et al. Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies. Oncotarget. 2015;6:14744–14753.
  • Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet. 2010;11:31–46.
  • Churi CR, Shroff R, Wang Y, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One. 2014;9:e115383.
  • Helena Verdaguer IB, Hierro C, Azaro A, et al. Impact of cholangiocarcinoma (CC) molecular heterogeneity on outcome during first-line chemotherapy and access to targeted therapies in early clinical trials (CT). J Clin Oncol. 2018;4091.
  • Loaiza-Bonilla A, Clayton E, Furth E, et al. Dramatic response to dabrafenib and trametinib combination in a BRAF V600E-mutated cholangiocarcinoma: implementation of a molecular tumour board and next-generation sequencing for personalized medicine. Ecancermedicalscience. 2014;8:479.
  • Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–728.
  • Makena MR, Ranjan A, Thirumala V, et al. Cancer stem cells: road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165339.
  • Phi LTH, Sari IN, Yang YG, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018;2018:5416923.
  • Peitzsch C, Tyutyunnykova A, Pantel K, et al. Cancer stem cells: the root of tumor recurrence and metastases. Semin Cancer Biol. 2017;44:10–24.
  • Shiozawa Y, Nie B, Pienta KJ, et al. Cancer stem cells and their role in metastasis. Pharmacol Ther. 2013;138:285–293.
  • Steg AD, Bevis KS, Katre AA, et al. Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res. 2012;18:869–881.
  • Yoshida GJ, Saya H. Therapeutic strategies targeting cancer stem cells. Cancer Sci. 2016;107:5–11.
  • Nagano O, Okazaki S, Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene. 2013;32:5191–5198.
  • Alisi A, Cho WC, Locatelli F, et al. Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma. Int J Mol Sci. 2013;14:24706–24725.
  • Abdullah LN, Chow EK. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med. 2013;2:3.
  • Peiris-Pages M, Martinez-Outschoorn UE, Pestell RG, et al. Cancer stem cell metabolism. Breast Cancer Res. 2016;18:55.
  • Deshmukh A, Deshpande K, Arfuso F, et al. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15:69.
  • Mayr C, Ocker M, Ritter M, et al. Biliary tract cancer stem cells - translational options and challenges. World J Gastroenterol. 2017;23:2470–2482.
  • Padthaisong S, Thanee M, Namwat N, et al. Overexpression of a panel of cancer stem cell markers enhances the predictive capability of the progression and recurrence in the early stage cholangiocarcinoma. J Transl Med. 2020;18:64.
  • Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012;30:372–378.
  • Mayr C, Wagner A, Loeffelberger M, et al. The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells. Oncotarget. 2016;7:745–758.
  • Kawamoto M, Umebayashi M, Tanaka H, et al. Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma. Anticancer Res. 2018;38:2739–2748.
  • Altves S, Yildiz HK, Vural HC. Interaction of the microbiota with the human body in health and diseases. Biosci Microbiota Food Health. 2020;39:23–32.
  • Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157:121–141.
  • Pushalkar S, Hundeyin M, Daley D, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8:403–416.
  • Riquelme E, Zhang Y, Zhang L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178:795–806 e712.
  • Cheng WY, Wu CY, Yu J. The role of gut microbiota in cancer treatment: friend or foe? Gut. 2020;69:1867–1876.
  • Sun L, Ma L, Ma Y, et al. Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein Cell. 2018;9:397–403.
  • Virtue AT, McCright SJ, Wright JM, et al. The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs. Sci Transl Med. 2019;11.
  • Brown K, Godovannyi A, Ma C, et al. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J. 2016;10:321–332.
  • Koh A, Molinaro A, Stahlman M, et al. Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 2018;175:947–961 e917.
  • Tilg H, Adolph TE, Gerner RR, et al. The intestinal microbiota in colorectal cancer. Cancer Cell. 2018;33:954–964.
  • Jin C, Lagoudas GK, Zhao C, et al. Commensal microbiota promote lung cancer development via gammadelta T cells. Cell. 2019;176:998–1013 e1016.
  • Ohtani N, Kawada N. Role of the gut-liver axis in liver inflammation, fibrosis, and cancer: a special focus on the gut microbiota relationship. Hepatol Commun. 2019;3:456–470.
  • Wiest R, Albillos A, Trauner M, et al. Corrigendum to “Targeting the gut-liver axis in liver disease” [J Hepatol 67 (2017) 1084-1103]. J Hepatol. 2018;68:1336.
  • Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol. 2012;18:337–346.
  • Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14:527–539.
  • Tripathi A, Debelius J, Brenner DA, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397–411.
  • Plieskatt JL, Deenonpoe R, Mulvenna JP, et al. Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome. FASEB J. 2013;27:4572–4584.
  • Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350:1084–1089.
  • Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–97.
  • Takemura N, Kawasaki T, Kunisawa J, et al. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat Commun. 2014;5:3492.
  • Stringer AM, Gibson RJ, Logan RM, et al. Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood). 2009;234:430–441.
  • Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30:R921–R925.
  • Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–4566.
  • Truffi M, Sorrentino L, Corsi F. Fibroblasts in the tumor microenvironment. Adv Exp Med Biol. 2020;1234:15–29.
  • Son B, Lee S, Youn H, et al. The role of tumor microenvironment in therapeutic resistance. Oncotarget. 2017;8:3933–3945.
  • Utaijaratrasmi P, Vaeteewoottacharn K, Tsunematsu T, et al. The microRNA-15a-PAI-2 axis in cholangiocarcinoma-associated fibroblasts promotes migration of cancer cells. Mol Cancer. 2018;17:10.
  • Thongchot S, Utaijaratrasmi P, Jamjantra P, et al. Interleukin-6 and hepatocyte growth factor produce from chromosomal aberrant cholangiocarcinoma-associated fibroblasts. Genomics and Genetics. 2020;13:33–43.
  • Fu H, Yang H, Zhang X, et al. The emerging roles of exosomes in tumor-stroma interaction. J Cancer Res Clin Oncol. 2016;142:1897–1907.
  • Ruivo CF, Adem B, Silva M, et al. The biology of cancer exosomes: insights and new perspectives. Cancer Res. 2017;77:6480–6488.
  • Van Den Boorn JG, Dassler J, Coch C, et al. Exosomes as nucleic acid nanocarriers. Adv Drug Deliv Rev. 2013;65:331–335.
  • Schey KL, Luther JM, Rose KL. Proteomics characterization of exosome cargo. Methods. 2015;87:75–82.
  • Puhka M, Takatalo M, Nordberg ME, et al. Metabolomic profiling of extracellular vesicles and alternative normalization methods reveal enriched metabolites and strategies to study prostate cancer-related changes. Theranostics. 2017;7:3824–3841.
  • Dai J, Su Y, Zhong S, et al. Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther. 2020;5:145.
  • Mimeault M, Batra SK. Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev. 2014;23:234–254.
  • Tai YL, Chen KC, Hsieh JT, et al. Exosomes in cancer development and clinical applications. Cancer Sci. 2018;109:2364–2374.
  • Rong L, Li R, Li S, et al. Immunosuppression of breast cancer cells mediated by transforming growth factor-beta in exosomes from cancer cells. Oncol Lett. 2016;11:500–504.
  • Li I, Nabet BY. Exosomes in the tumor microenvironment as mediators of cancer therapy resistance. Mol Cancer. 2019;18:32.
  • Wang J, De Veirman K, Faict S, et al. Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression. J Pathol. 2016;239:162–173.
  • Zhao H, Yang L, Baddour J, et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 2016;5:e10250.
  • Richards KE, Zeleniak AE, Fishel ML, et al. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–1778.
  • Chen JH, Xiang JY, Ding GP, et al. Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-alpha and perforin. J Zhejiang Univ Sci B. 2016;17:537–544.
  • Hodson R. Precision medicine. Nature. 2016;537:S49.
  • Crisci S, Amitrano F, Saggese M, et al. Overview of current targeted anti-cancer drugs for therapy in onco-hematology. Medicina (Kaunas). 2019;55.
  • Paananen J, Fortino V. An omics perspective on drug target discovery platforms. Brief Bioinform. 2019.
  • Wheelock CE, Goss VM, Balgoma D, et al. Application of ‘omics technologies to biomarker discovery in inflammatory lung diseases. Eur Respir J. 2013;42:802–825.
  • Scharfe CPI, Tremmel R, Schwab M, et al. Genetic variation in human drug-related genes. Genome Med. 2017;9:117.
  • Roden DM, Wilke RA, Kroemer HK, et al. Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011;123:1661–1670.
  • Wardell CP, Fujita M, Yamada T, et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 2018;68:959–969.
  • Nepal C, O’Rourke CJ, Oliveira D, et al. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology. 2018;68:949–963.
  • Duangkumpha K, Stoll T, Phetcharaburanin J, et al. Discovery and qualification of serum protein biomarker candidates for cholangiocarcinoma diagnosis. J Proteome Res. 2019;18:3305–3316.
  • Duangkumpha K, Stoll T, Phetcharaburanin J, et al. Urine proteomics study reveals potential biomarkers for the differential diagnosis of cholangiocarcinoma and periductal fibrosis. PLoS One. 2019;14:e0221024.
  • Proungvitaya S, Klinthong W, Proungvitaya T, et al. High expression of CCDC25 in cholangiocarcinoma tissue samples. Oncol Lett. 2017;14:2566–2572.
  • Tummanatsakun D, Proungvitaya T, Roytrakul S, et al. Serum apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) level as a potential biomarker of cholangiocarcinoma. Biomolecules. 2019;9.
  • Sanmai S, Proungvitaya T, Limpaiboon T, et al. Serum pyruvate dehydrogenase kinase as a prognostic marker for cholangiocarcinoma. Oncol Lett. 2019;17:5275–5282.

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