Substitutionally inert Pt(IV)
prodrugs, combining bioactive axial
ligands with Pt(IV) derivatives of antitumor Pt(II) compounds, represent a new generation of anticancer drugs. The rationale behind these
prodrugs is to release, by reductive elimination inside the
cancer cell, an active Pt(II) drug which binds nuclear
DNA as well as bioactive
ligands that may potentiate toxic effects of the Pt(II) drugs by an independent pathway.
Platinum prodrugs, such as Pt(IV) derivatives of
cisplatin containing axial
valproic acid (VPA)
ligands, destroy
cancer cells with greater efficacy than conventional
cisplatin. These axial
ligands were chosen because VPA inhibits
histone deacetylase (HDAC) activity, thereby decondensing
chromatin and subsequently increasing the accessibility of
DNA within
chromatin to
DNA-binding agents. We examined the mechanism of cytotoxic activity of Pt(IV) derivatives of
cisplatin with VPA axial
ligands. Particular attention was paid to the role of the VPA
ligand in these Pt(IV)
prodrugs in the mechanism underlying their toxic effects in human ovarian
tumor cells. We demonstrate that (i) treatment of the cells with these
prodrugs resulted in enhanced
histone H3 acetylation and decondensation of
heterochromatin markedly more effectively than free VPA; (ii) of the total Pt inside the cells, a considerably higher fraction of Pt from the Pt(IV)-VPA conjugates is bound to
DNA than from the conjugates with biologically inactive
ligands. The results indicate that the enhanced cytotoxicity of the Pt(IV)-VPA conjugates is a consequence of several processes involving enhanced cellular accumulation, downregulation of HDACs and yet other biochemical processes (not involving HDACs) which may potentiate antitumor effects.