Pt(IV) Pro-Drugs with an Axial HDAC Inhibitor Demonstrate Multimodal Mechanisms Involving DNA Damage and a Poptosis Independent of Cisplatin Resistance in A2780/A2780cis Cells
Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence
1.4 CHEMICAL SCIENCES, Organic Chemistry, Biochemistry and molecular biology
Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A – C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.
Almotairy, A.R.Z. et al. . (2020) Pt(IV) Pro-Drugs with an Axial HDAC Inhibitor Demonstrate Multimodal Mechanisms Involving DNA Damage and a Poptosis Independent of Cisplatin Resistance in A2780/A2780cis Cells, Journal of Inorganic Biochemistry, 210 (2020) DOI:10.1016/j.jinorgbio.2020.111125
Journal of Inorganic Biochemistry, 210 (2020) 111125