title: Single pre-treatment with hypericin, a St. John's wort secondary metabolite, attenuates cisplatin- and mitoxantrone-induced cell death in A2780, A2780cis and HL-60 cells.
abstract: St. John's wort (SJW, Hypericum perforatum L.) is a commonly used natural antidepressant responsible for the altered toxicity of some anticancer agents. These interactions have been primarily attributed to the hyperforin-mediated induction of some pharmacokinetic mechanisms. However, as previously demonstrated by our group, hypericin induces the expression of two ABC transporters: multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). Because cisplatin (CDDP) and mitoxantrone (MTX) are potential substrates of ABC transporters, we investigated the effect of 24h hypericin pre-treatment on the cytotoxicity of CDDP and MTX in human cancer cell lines. CDDP-sensitive and -resistant ovarian adenocarcinoma cell lines A2780/A2780cis, together with HL-60 promyelocytic leukemia cells and ABCG2-over-expressing cBCRP subclone, were used in our experiments. We present CDDP cytotoxicity attenuated by hypericin pre-treatment in both A2780 and A2780cis cells and MTX cytotoxicity in HL-60 cells. In contrast, hypericin potentiated MTX-induced death in cBCRP cells. Interestingly, hypericin did not restore cell proliferation in rescued cells. Nevertheless, hypericin did increase the expression of MRP1 transporter in A2780 and A2780cis cells indicating the impact of hypericin on certain resistance mechanisms. Additionally, our results indicate that hypericin may be the potential substrate of BCRP transporter. In conclusion, for the first time, we report the ability of hypericin to affect the onset and/or progress of CDDP- and MTX-induced cell death, despite strong cell cycle arrest. Thus, hypericin represents another SJW metabolite that might be able to affect the effectiveness of anti-cancer drugs and that could interact with ABC transporters, particularly with BCRP.
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: zuzana.papcova@student.upjs.sk.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Jendželovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, 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, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: lucia.hilovska@student.upjs.sk.
authors.forename: Lucia
authors.initials: L
authors.lastname: Hiľovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: jan.koval@upjs.sk.
authors.forename: Ján
authors.initials: J
authors.lastname: Kovaľ
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: jaromir.mikes@upjs.sk.
authors.forename: Jaromír
authors.initials: J
authors.lastname: Mikeš
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, 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: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000873:Anthracenes; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D020902:Hypericum; D008942:Mitoxantrone / Q000494:pharmacology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000873:Anthracenes; D000970:Antineoplastic Agents; D002945:Cisplatin; D008942:Mitoxantrone; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010569:Perylene; D012333:RNA, Messenger; C116614:ABCG2 protein, human; C004965:hypericin; C421109:multidrug resistance-associated protein 1
keywords: BCRP; Cisplatin; Hypericin; MRP; Mitoxantrone; St. John’s wort