Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates

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.

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

“…The presence of a single bioactive ligand phenylbutyrate or octanoate in the Pt IV compounds I or II (Figure ) led to significant reduction of the IC 50 values in comparison to cisplatin in all six malignant cell lines tested in this work [the human ovarian carcinoma cisplatin‐sensitive A2780 cells, cisplatin‐resistant A2780cisR (cisplatin‐resistant variant of A2780 cells), human cervical carcinoma HeLa cells, human breast cancer MCF‐7 cells, human colorectal carcinoma cells HCT‐116, and highly invasive breast carcinoma MDA‐MB‐231 cells], with the octanoate‐derivative II being more potent than phenylbutyrate analog I . These results are in agreement with recently published data . Importantly, the combination of both active groups (phenylbutyrate and octanoate) in compound III resulted in a further increase in toxicity/antiproliferative activity determined by MTT assay.…”

“…It has been shown that the toxic effect of some Pt IV derivatives of cisplatin, oxaliplatin, or carboplatin in cancer cells is accompanied by the mitochondrial membrane potential disruption, which affects mitochondrial functions . In cells undergoing apoptosis, the loss of mitochondrial membrane potential is often accompanied by the release of cytochrome c from mitochondria into the cytosol and represents an early step in the mitochondria‐dependent apoptotic process.…”

“…Pt IV derivatives of cisplatin with either one or two 4‐phenylbutyrate (PhB) ligands in the axial positions showed inhibitory effects towards histone deacetylases (HDACs), thus potentiating the anticancer effect of the platinum moiety . Moreover, the two axial octanoate residues contained in the Pt complex cis , trans , cis ‐[Pt(NH 3 ) 2 (OA) 2 Cl 2 ] inhibit effectively DNA methyltransferase(s), thus inducing global DNA hypermethylation . Both these epigenetic factors, that is, histone acetylation and DNA methylation, significantly contribute to the biological activity of these Pt derivatives in a synergistic way.…”

“…The cells were treated with the compounds for 24 h at the concentrations corresponding to their respective IC 50 values, and twice and thrice their values; DNA was isolated as described in the Material and Methods section and the methylation level was quantified colorimetrically by employing the commercial Imprint DNA methylation kit. As shown in Figure B, no effect on the level of DNA methylation was observed after the treatment with cisplatin, in accord with the previously published results . As expected, a considerably increased level of DNA methylation was observed after the treatment with 1, 1.9, and 2.9 μ m II ; the effect was concentration dependent.…”

“…Recently, Pt IV complex cis , trans , cis ‐[Pt(NH 3 ) 2 (OA) 2 Cl 2 ] bearing octanoate (OA) as axial ligands has been reported to act as an effective anticancer compound in vitro and in vivo . The high potency of this compound is a consequence of several factors such as enhanced cellular accumulation, enhanced DNA platination, and DNA hypermethylation owing to the effect of octanoic acid.…”