New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells

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

“…It was shown in our previous report 11 that the total accumulation of free VPA after 24 h exposure of the cells was more than three orders of magnitude lower than after comparable exposure to Pt(IV)diVPA since at neutral pH VPA is monoanionic and therefore does not efficiently accumulate in tumor cells. The non-branched isomer of VPA, OA, is monoanionic as well so that it is reasonable to expect that free OA will accumulate in tumor cells with markedly reduced efficiency in comparison with lipophilic Pt(IV) derivatives of cisplatin containing axial OA ligands.…”

“…The IC 50 values found for Pt(IV)AcOA were in the submicromolar range except for the IC 50 value found for CHO-K1 cells (IC 50 was ~1 µM). The IC 50 values for Pt(IV)diOA were significantly lower than those of its isomer Pt(IV)diVPA in the A2780 cell line (0.041 ± 0.001 vs. 0.25 ± 0.09), A2780cisR (0.029 ± 0.002 vs. 0.3 ± 0.1) and MCF-7 (0.038 ± 0.006 vs. 0.9 ± 0.3) 11 .…”

“…In contrast, the replacement of axial acetato ligands in Pt(IV)diAc by one or two OA groups transformed this Pt(IV) derivative of cisplatin into hydrophobic species Pt(IV)AcOA and Pt(IV)diOA (partition preferentially into octanol). Interestingly, logP values found for Pt(IV)AcVPA and Pt(IV)diVPA 11 were 0.17 and 0.25 indicating that Pt(IV) complexes containing branched C8 chain were less hydrophobic than their octanoato derivatives containing linear C8 aliphatic chain. This is also evident by noting that despite having six carbons less, Pt(IV)AcOA has similar log P value as Pt(IV)diVPA.…”

“…In other words, yet another factor in addition to enhanced cellular accumulation had to be responsible for enhanced cytotoxicity of these Pt(IV) prodrugs compared with Pt(IV)diAc or cisplatin. It was shown 11, 12 in the case of other Pt(IV) derivatives of cisplatin, having the branched isomer of OA, i.e. VPA, that its enhanced cytotoxicity is a consequence of several processes involving besides enhanced cellular accumulation also epigenetic processes.…”

“…It has been shown 11, 12 that the enhanced cytotoxicity of the cis , cis , trans -[Pt(IV)(NH 3 ) 2 Cl 2 (VPA) 2 ] conjugate [Pt(IV)diVPA] is a consequence of several processes. They involve enhanced cellular accumulation, downregulation of histone deacetylases (HDACs) and yet other biochemical processes (not involving HDACs) which may potentiate antitumor effects.…”