Abstract 4485: Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian cancer

Abstract

Abstract Background: Platinum(IV) [Pt(IV)] complexes are one of the attractive next-generation anticancer drugs. Beside Pt(II)-based drugs such as cisplatin, carboplatin, and oxaliplatin, Pt(IV) complexes show less adverse effects and can be administrated orally. In addition, because Pt(IV) complexes adopt octahedral coordination geometry, it also have an advantage that can be coordinated with more functional ligands than Pt(II) complexes. These different features prompted us to investigate the effectiveness of Pt(IV) complexes on cisplatin-resistant cancer cells with its mechanisms. This study aims to elucidate the anti-cancer effects of Pt(IV) complexes. Materials and Methods: The cytotoxicity of cis-diammine-tetrachloro-Pt(IV) [cis-Pt(IV)] and cisplatin was determined using human ovarian cancer cell lines (A2780), and its cisplatin-resistant subline (A2780cis), with their influx/efflux patterns using ICP-MS. Pt-DNA-crosslink formation was also determined by agarose gel electrophoresis, in which the crosslink was quantified by decrease of ethidium bromide staining of DNA. Results and Discussion: Cisplatin completely failed to decrease the survival of A2780cis cells at a concentration that killed A2780, whereas cis-Pt(IV) exerted cytotoxicity in both cell lines. Pt-DNA-crosslink formation assay showed cis-Pt(IV) bound to DNA only in the presence of reductant such as glutathione (GSH) or ascorbic acid, indicating cisplatin production. However, it is also known excess amount of GSH suppress DNA binding of cisplatin. Indeed, intracellular GSH level in A2780cis cells was about 3 times higher as compared with A2780 cells; therefore cisplatin would be inactivated in A2780cis cells. These findings suggest that cis-Pt(IV) is actually reduced to cisplatin in GSH-rich environment and then induce cytotoxicity by somehow escaping from GSH-dependent inactivation. Pt(IV)-specific subcellular distribution might contribute this paradoxical advantageous effect of GSH on cis-Pt(IV). Intracellular accumulation of Pt was reduced by competing a related transporter CTR1 by copper in cis-Pt(IV) treatment, whereas cytotoxicity was not suppressed. Therefore CTR1 is involved in the intake of Pt complexes including cis-Pt(IV), but the alternative pathway(s) could be responsible for anti-cancer effect of Pt(IV) complexes. Citation Format: Yoshinori Okamoto, Takao Tobe, Koji Ueda, Nakao Kojima. Anticancer effect of platinum(IV) complex against cisplatin-resistant human ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4485. doi:10.1158/1538-7445.AM2015-4485