title: Unique Use of Alkylation for Chemo-Redox Activity by a Pt(IV) Prodrug.
abstract: Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols.
authors.affiliation: NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA, 30602, USA), Fax: (+1) 706-542-9454.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Pathak
authors.affiliation: NanoTherapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA, 30602, USA), Fax: (+1) 706-542-9454. shanta@uga.edu.
authors.forename: Shanta
authors.initials: S
authors.lastname: Dhar
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D004260:DNA Repair; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D008928:Mitochondria / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011355:Prodrugs; C000609050:platin-B; D005978:Glutathione; D002945:Cisplatin
keywords: DNA repair; alkylating agent; cancer; cisplatin; glutathione