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

Francisco NavasAna Chocarro-CalvoPatricia Iglesias-HernándezPaloma Fernández-GarcíaVictoria MoralesJosé Manuel García-MartínezRaúl SanzAntonio De la ViejaCustodia García-JiménezRafael A García-Muñoz
Published in: Journal of medicinal chemistry (2024)
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.
Keyphrases
  • dna damage
  • magnetic resonance
  • computed tomography
  • induced apoptosis
  • cell proliferation
  • cancer therapy
  • endoplasmic reticulum stress
  • diabetic rats