title: Synthesis of a monofunctional platinum compound and its activity alone and in combination with phytochemicals in ovarian tumor models.
abstract: Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. In this study, a new monofunctional planaramineplatinum(II) complex, namely tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (coded as LH3), was synthesised and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistant A2780 (A2780(ZD0473R)) cancer cell lines, alone and in combination with the phytochemicals curcumin, genistein and resveratrol. Cellular levels of glutathione in A2780 and A2780(cisR) cell lines before and after treatment with LH3 and its combinations with genistein and curcumin were also determined. Interaction of the compounds with salmon sperm DNA, pBR322 plasmid DNA and damage to DNA in A2780 and A2780(cisR) cells due to interaction with LH3-alone and in combination with phytochemicals were also investigated. LH3 was found to be much more active than cisplatin against the resistant tumor models and greatest synergism in activity was observed when combinations of LH3 with genistein and curcumin were administered as a bolus. For combinations of LH3 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were found to be greater in the resistant A2780(cisR) cell line than in the parental A2780 cell line. Greater activity of LH3 than cisplatin against the resistant ovarian cell lines indicates that it may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy.
authors.affiliation: Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia.
authors.forename: Laila
authors.initials: L
authors.lastname: Arzuman
authors.affiliation: Sydney Cancer Centre, Concord Repatriation Hospital, Concord, NSW, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Beale
authors.affiliation: Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia.
authors.forename: Jun Qing
authors.initials: JQ
authors.lastname: Yu
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Proschogo
authors.affiliation: Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia Fazlul.Huq@sydney.edu.au.
authors.forename: Fazlul
authors.initials: F
authors.lastname: Huq
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015245:Deoxyribonuclease BamHI / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D019833:Genistein / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D064209:Phytochemicals / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D064209:Phytochemicals; D017671:Platinum Compounds; D013267:Stilbenes; C110525:amminedichloro(2-methylpyridine)platinum(II); C000596185:tris(8-hydroxyquinoline)monochloroplatinum(II); D004247:DNA; D019833:Genistein; D015245:Deoxyribonuclease BamHI; D005978:Glutathione; D003474:Curcumin; D002945:Cisplatin; D000077185:Resveratrol
keywords: 8-Hydroxyquinoline; drug combination; drug resistance; monofunctional platinum; ovarian cancer