Investigations into the cellular mechanism of action of transplanaramines of the type trans-[Pt (O₂CR)₂ (L) (L’)]

B36

The current work investigates the influence of transplanaramine (TPA) platinum compounds of structure trans-[Pt (O₂CR)₂ (L) (L’)], (L=NH₃, L’= pyridine, quinoline, isoquinoline; L = L ‘ = pyridine; R = H, CH₃, CH₂OH) on growth and viability of HCT116 human colon carcinoma and A2780 human ovarian carcinoma cells as well as their putative mechanism(s) of cytotoxicity. A series of structural analogs was examined with a focus on the contribution of the carboxylate leaving group to drug action. The compounds, as a class, have been shown to induce cell death through caspase-dependent apoptosis, with activation of both caspase 3 and caspase 9 and concomitant PARP cleavage. Both A2780 and HCT116 WT cell lines are most sensitive to trans-[Pt (O₂CH)₂(NH₃)(Isq)], which may be related to its enhanced cellular accumulation. The enhanced cytotoxicity of trans-[Pt(O₂CH)₂(NH₃)(Isq)] compared to its isostructural -O₂CCH₃ analog may be a consequence of its increased hydrolytic activation, enhanced cellular uptake, interstrand cross-linking and abortive efforts by the cell to repair the cross linked DNA. Previous studies have shown higher levels of cytotoxicity specific tumor types when compared to cisplatin. Here we examine the contributions of molecular pathways to the cytotoxic effect of transplanaramines as compared to cisplatin and oxaliplatin. This data suggests that the trans-[Pt (O₂CH)₂(NH₃)(Isq)] compound is a possible candidate for clinical development.