Abstract
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.
Highlights
Cisplatin and its homologs are powerful anticancer drugs, but their therapeutic index is very narrow due to heavy side effects
The IC50 values found for Pt(IV)diOA conjugate ranged from 17 nM in colon carcinoma cells HCT-116 up to 140 nM in nonmalignant Chinese hamster ovary cells CHO-K1, i.e. that these IC50 values were by one or two orders of magnitude lower than those found for cisplatin
Our study demonstrates that the Pt(IV) derivative of cisplatin, with two axial OA ligands, is a very potent cytotoxic agent against many different cancer cell lines, which overcomes resistance to cisplatin (Table 1) and exhibits promising in vivo antitumor activity (Table 4)
Summary
Cisplatin and its homologs are powerful anticancer drugs, but their therapeutic index is very narrow due to heavy side effects. A higher fraction of the Pt(IV) complexes may reach tumor cells intact, where they undergo reduction by intracellular reductants[3, 4] Their axial ligands can affect the cellular accumulation of Pt(IV) compounds due to their enhanced lipophilicity (the influx occurs mainly by passive diffusion)[5]. In cellulo studies showed that the cisplatin-based Pt(IV) complexes, having medium-chain fatty acids (MCFAs) axial ligands, namely octanoato (OA) and its branched isomer valproato (VPA), possess remarkable antiproliferative activity[9, 10] It has been shown[11, 12] that the enhanced cytotoxicity of the cis, cis, trans-[Pt(IV) (NH3)2Cl2(VPA)2] conjugate [Pt(IV)diVPA] is a consequence of several processes. Our studies suggest that strategies based on platinum(IV) prodrugs combined with epigenetically active compounds synergistically improve efficacy
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