Abstract
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)(2)Cl-2(PBA)(2)] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)(2)Cl-2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)(2)Cl-2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)(2)Cl-2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, gamma-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.
| Original language | English (Ireland) |
|---|---|
| Article number | 111125 |
| Journal | Journal Of Inorganic Biochemistry |
| Volume | 210 |
| DOIs | |
| Publication status | Published - 1 Sep 2020 |
Keywords
- Apoptosis
- Cytotoxicity
- DNA damage
- Histone deacetylase inhibitor
- Platinum(IV) complexes
- Reactive oxygen species
Authors (Note for portal: view the doc link for the full list of authors)
- Authors
- Almotairy, ARZ,Montagner, D,Morrison, L,Devereux, M,Howe, O,Erxleben, A
