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Chemosensitivity Determinants of Irinotecan Hydrochloride in Hepatocellular Carcinoma Cell Lines
Author(s) -
Takahata Takenori,
Ookawa Keizou,
Suto Koji,
Tanaka Masanori,
Yano Hirohisa,
Nakashima Osamu,
Kojiro Masamichi,
Tamura Yoshihiro,
Tateishi Tomonori,
Sakata Yuh,
Fukuda Shinsaku
Publication year - 2008
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2007.00199.x
Subject(s) - naringenin , cyp3a4 , abcg2 , pharmacology , chemistry , hepatocellular carcinoma , cell culture , irinotecan , cytochrome p450 , grapefruit juice , cancer research , biology , enzyme , medicine , cancer , biochemistry , pharmacokinetics , atp binding cassette transporter , colorectal cancer , transporter , genetics , flavonoid , gene , antioxidant
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.