We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs.

Department of Biophysics Centre of the Region Hana for Biotechnological Agricultural Research Faculty of Science Palacky University 17 listopadu 12 CZ 77146 Olomouc Czech Republic

Dipartimento di Scienze del Farmaco Universita di Padova Via Marzolo 5 35131 Padova Italy

Dipartimento di Scienze e Innovazione Tecnologica Universita del Piemonte Orientale A Avogadro Viale T Michel 11 15121 Alessandria Italy

Institute for Drug Research School of Pharmacy The Hebrew University Jerusalem 91120 Israel

Institute of Biophysics Academy of Sciences of the Czech Republic v v i Kralovopolska 135 CZ 61265 Brno Czech Republic

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