title: Proadifen sensitizes resistant ovarian adenocarcinoma cells to cisplatin.
abstract: Proadifen (SKF-525A) is a P450 monooxygenase inhibitor with potential anti-proliferative activity and the ability to potentiate the toxicity of hypericin-mediated photodynamic therapy and mitoxantrone via alteration of ABC transport proteins. Elevated expression of some ABC transporters may also determine the efficacy of cisplatin-based chemotherapy. Thus, the purpose of this study was to investigate the ability of proadifen to sensitize A2780 and A2780cis ovarian cancer cells to cisplatin (CDDP). Herein, we show for the first time that proadifen sensitized resistant ovarian cancer cells to CDDP-induced cell death. The chemosensitizing effect of proadifen on CDDP action was also confirmed by MTT assays in multicellular spheroids. The possible mechanisms responsible for the enhanced cytotoxicity of proadifen/CDDP combined treatment may be attributed to a decrease of reduced relative glutathione levels, downregulation of multidrug resistance-associated proteins 1 and 2 (MRP1, MRP2) and attenuation of survivin expression. Taken together, our results indicate that proadifen is a promising compound for further in vivo experiments related to overcoming multidrug resistance and sensitization of resistant ovarian carcinoma to CDDP.
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: rastislav.jendzelovsky@upjs.sk.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendželovský
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: zuzana.jendzelovska@upjs.sk.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Jendželovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: lhilovska@hotmail.com.
authors.forename: Lucia
authors.initials: L
authors.lastname: Hiľovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: tahanko@yahoo.com.
authors.forename: Ján
authors.initials: J
authors.lastname: Kovaľ
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: jaromir.mikes@gmail.com.
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikeš
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: peter.fedorocko@upjs.sk.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedoročko
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011335:Proadifen / Q000494:pharmacology*; D000077022:Survivin; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D002945:Cisplatin; D051544:Cytochrome P-450 CYP3A; D051034:Inhibitor of Apoptosis Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011335:Proadifen; D000077022:Survivin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C000715087:ABCC2 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; C510163:CYP3A4 protein, human; C421109:multidrug resistance-associated protein 1
keywords: Cisplatin; Glutathione; MRP1; MRP2; Proadifen; Survivin