title: Cisplatin enhances the anticancer effect of beta-lapachone by upregulating NQO1.
abstract: NAD(P)H:quinone oxidoreductase (NQO1) has been reported to play an important role in cell death caused by beta-lapachone (beta-lap), 3,4-dihydro-22,2-dimethyl-2H-naphthol[1,22b]pyran-5,6-dione. This study investigated whether cisplatin (cis-diamminedichloroplatinum) sensitizes cancer cells to beta-lap by upregulating NQO1. The cytotoxicity of cisplatin and beta-lap alone or in combination against FSaII fibrosarcoma cells of C3H mice in vitro was determined with a clonogenic survival assay and assessment of gamma-H2AX foci formation, a hallmark of DNA double-strand breaks. The cellular sensitivity to beta-lap progressively increased during the 24 h after cisplatin treatment. The expression and enzymatic activity of NQO1 also increased during the 24 h after cisplatin treatment, and dicoumarol, an inhibitor of NQO1, was found to nullify the cisplatin-induced increase in beta-lap sensitivity. The role of NQO1 in the cell death caused by beta-lap alone or in combination with cisplatin was further elucidated using NQO1-positive and NQO1-negative MDA-MB-231 human breast cancer cells. Cisplatin increased the sensitivity of the NQO1-positive but not the NQO1-negative MDA-MB-231 cells to beta-lap treatment. Combined treatment with cisplatin and beta-lap suppressed the growth of FSaII tumors in the legs of C3H mice in a manner greater than additive. It is concluded that cisplatin markedly increases the sensitivity of cancer to beta-lap in vitro and in vivo by upregulating NQO1.
authors.affiliation: Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Academic Health Center, Minneapolis, Minnesota, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Terai
authors.forename: Guang-Zhi
authors.initials: GZ
authors.lastname: Dong
authors.forename: Eun-Taex
authors.initials: ET
authors.lastname: Oh
authors.forename: Moon-Taek
authors.initials: MT
authors.lastname: Park
authors.forename: Yeunhwa
authors.initials: Y
authors.lastname: Gu
authors.forename: Chang Won
authors.initials: CW
authors.lastname: Song
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006657:Histones / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D006657:Histones; D009285:Naphthoquinones; C475961:gamma-H2AX protein, mouse; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D002945:Cisplatin