title: Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers.
abstract: Phosphaplatins, platinum(II) and platinum(IV) complexes coordinated to a pyrophosphate moiety, exhibit excellent antitumor activities against a variety of cancers. To determine whether phosphaplatins trigger resistance to treatment by engaging DNA damage repair genes, a yeast genome-wide fitness assay was used. Treatment of yeast cells with pyrodach-2 (D2) or pyrodach-4 (D4) revealed no particular sensitivity to nucleotide excision repair, homologous recombination repair, or postreplication repair when compared with platin control compounds. Also, TNF receptor superfamily member 6 (FAS) protein was overexpressed in phosphaplatin-treated ovarian tumor cells, and platinum colocalized with FAS protein in lipid rafts. An overactivation of sphingomyelinase (ASMase) was noted in the treated cells, indicating participation of an extrinsic apoptotic mechanism due to increased ceramide release. Our results indicate that DNA is not the target of phosphaplatins and accordingly, that phosphaplatins might not cause resistance to treatment. Activation of ASMase and FAS along with the colocalization of platinum with FAS in lipid rafts support an extrinsic apoptotic signaling mechanism that is mediated by phosphaplatins.
authors.affiliation: Departments of Biology and Biochemistry, University of Houston , Houston, Texas 77204, United States.
authors.forename: Rathindra N
authors.initials: RN
authors.lastname: Bose
authors.affiliation: Departments of Biology and Biochemistry, University of Houston , Houston, Texas 77204, United States.
authors.forename: Shadi
authors.initials: S
authors.lastname: Moghaddas
authors.affiliation: Departments of Biology and Biochemistry, University of Houston , Houston, Texas 77204, United States.
authors.forename: Louiza
authors.initials: L
authors.lastname: Belkacemi
authors.affiliation: Departments of Biology and Biochemistry, University of Houston , Houston, Texas 77204, United States.
authors.forename: Swarnendu
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Ohio University , Athens, Ohio 45701, United States.
authors.forename: Nyssa R
authors.initials: NR
authors.lastname: Adams
authors.affiliation: Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Ohio University , Athens, Ohio 45701, United States.
authors.forename: Pooja
authors.initials: P
authors.lastname: Majmudar
authors.affiliation: Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Ohio University , Athens, Ohio 45701, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: McCall
authors.affiliation: Departments of Biology and Biochemistry, University of Houston , Houston, Texas 77204, United States.
authors.forename: Homa
authors.initials: H
authors.lastname: Dezvareh
authors.affiliation: Department of Pharmaceutical Sciences, University of British Columbia , Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D009944:Organoplatinum Compounds; D019014:fas Receptor; D004247:DNA; D013108:Sphingomyelin Phosphodiesterase