Promising Anticancer Prodrugs Based on Pt(IV) Complexes with Bis-organosilane Ligands in Axial Positions

We report two novel prodrug Pt(IV) complexes with bis-organosilane
ligands in axial positions: cis-dichloro(diamine)-trans-[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1)
and cis-dichloro(diisopropylamine)-trans-[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2).
Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity
against colon cancer cells (HCT 116 and HT-29) compared with cisplatin
and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity
toward cancer cells and lower toxicity on nontumorigenic intestinal
cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2
outperformed cisplatin in reducing tumor growth at lower concentrations,
with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced
permanent DNA damage independent of p53 levels. DNA damage such as
double-strand breaks marked by histone gH2Ax was permanent after treatment
with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects.
Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure
to
biological reductants supports its superior biological response. These
findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs
with enhanced activity and specificity, offering therapeutic opportunities
beyond conventional Pt drugs.