title: Chemosensitivity determinants of irinotecan hydrochloride in hepatocellular carcinoma cell lines.
abstract: Irinotecan hydrochloride (CPT-11) is an effective anticancer drug, and its metabolic pathway has been well studied. Nevertheless, in human hepatocellular carcinoma (HCC), its cytotoxicity is less well studied and the determination of its chemosensitivity is unclear. We, therefore, examined chemosensitivities of HCC cell lines for CPT-11 and SN-38, and mRNA expressions of several molecules in their metabolic pathway. Three markers were found to correlate well with chemosensitivity: breast cancer resistance protein (BCRP), cytochrome P450 (CYP) 3A4 and uridine diphosphate-glucuronosyl transferase (UGT) 1A1. Next, CYP3A4/UGT1A1/BCRP inhibitor naringenin and BCRP inhibitor elacridar were tested for enhancement of their chemosensitivity. Both of naringenin and elacridar separately enhanced the sensitivity for CPT-11 and SN-38 in KYN-2 cells abundantly expressing BCRP, CYP3A4/5 and UGT1A1, but not in KYN-1 cells expressing lower levels. However, naringenin had little effect on the sensitivity in JHH-4 and HLE cells with higher CYP3A4/5 and lower UGT1A1 and BCRP expression. On the other hand, naringenin and elacridar significantly increased the chemosensitivity for CPT-11 and SN-38 in the KYN-1-derived cells artificially overexpressing BCRP. Furthermore, flow cytometric analysis showed that naringenin raised intracellular accumulation of CPT-11 as well as elacridar. Those results suggest that BCRP is one of the chemosensitivity determinants of CPT-11 in HCC cells and its inhibition might be critical for cells expressing abundant BCRP.
authors.affiliation: First Department of Internal Medicine, and Department of Clinical Pharmacology, Hirosaki University School of Medicine, Aomori, Japan. takatake@cc.hirosaki-u.ac.jp
authors.forename: Takenori
authors.initials: T
authors.lastname: Takahata
authors.forename: Keizou
authors.initials: K
authors.lastname: Ookawa
authors.forename: Koji
authors.initials: K
authors.lastname: Suto
authors.forename: Masanori
authors.initials: M
authors.lastname: Tanaka
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakashima
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kojiro
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tamura
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
authors.forename: Yuh
authors.initials: Y
authors.lastname: Sakata
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Fukuda
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014162:Transfection; D000099148:UGT1A1 Enzyme
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D044950:Flavanones; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D000099148:UGT1A1 Enzyme; C116614:ABCG2 protein, human; C510163:CYP3A4 protein, human; C005273:naringenin; C083501:Elacridar