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Drug Metab Dispos. 2018 Mar;46(3):214-222. doi: 10.1124/dmd.117.078402. Epub 2017 Dec 15.

Impact of Breast Cancer Resistance Protein Expression on the In Vitro Efficacy of Anticancer Drugs in Pancreatic Cancer Cell Lines.

Author information

1
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.W., T.N., I.T.); and Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan (I.W., N.I., N.Y.).
2
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (I.W., T.N., I.T.); and Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan (I.W., N.I., N.Y.) tamai@p.kanazawa-u.ac.jp.

Abstract

Breast cancer resistance protein (BCRP) overexpression confers multidrug resistance to cancer cells, and the efficacy of anticancer drugs has been reported to be significantly affected by BCRP in cell lines transfected with BCRP or selected with drugs. It is unclear whether the in vitro efficacy of anticancer drugs is affected by endogenous BCRP, although cancer cell line panels consisting of defined tumor cell lines with endogenous BCRP have been used to screen for anticancer drugs in the pharmaceutical industry. We assessed the impact of BCRP expression on efficacy of anticancer drugs using pancreatic cancer cell lines expressing varying levels of endogenous BCRP. Pancreatic cancer cell lines were selected from the Cancer Cell Line Encyclopedia (CCLE). The EC50 of 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, and mitoxantrone decreased in the presence of a BCRP inhibitor in PANC-1 and AsPC-1 cells, which exhibit high BCRP expression. However, no significant alterations in EC50 were observed in HPAF-II, SW 1990, and MIA PaCa-2, which show moderate or low BCRP expression. The shift of EC50 of anticancer drugs with and without a BCRP inhibitor increased with an increase of BCRP mRNA expression levels; however, the shift was obvious only in cells highly expressing BCRP. Thus, the in vitro efficacy of anticancer drugs on cell proliferation may be minimally affected by BCRP in most pancreatic cancer cell lines, considering that 72% of pancreatic cancer cell lines in CCLE show moderate or low BCRP expression. The effect of BCRP should be carefully evaluated in pancreatic cell lines that highly express BCRP.

PMID:
29246888
DOI:
10.1124/dmd.117.078402
[Indexed for MEDLINE]

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