Dual- or multi-action PtIV
prodrugs represent a new generation of
platinum anticancer drugs. The important property of these PtIV
prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial
ligands. This work describes the synthesis and some
biological properties of a "triple-action"
prodrug that releases in
cancer cells
cisplatin and two different epigenetically acting moieties,
octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the PtIV
prodrug results in a selective and high potency in
tumor cells including those resistant to
cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9 nm (HCT-116) to 74 nm (MDA-MB-231)]. It is also demonstrated that cellular activation of the PtIV
prodrug results in covalent modification of
DNA through the release of the
platinum moiety accompanied by inhibition of the activity of
histone deacetylases caused by phenylbutyrate and by global hypermethylation of
DNA by
octanoate. Thus, the PtIV
prodrug introduced in this study acts as a true "multi-action"
prodrug, which is over two orders of magnitude more active than clinically used
cisplatin, in both 2D monolayer culture and 3D spheroid
cancer cells.