Almotairy, Awatif Rashed Z. and Montagner, Diego and Morrison, Liam and Devereux, Michael and Erxleben, Andrea (2020) Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells Author links open overlay panel. Journal of Inorganic Biochemistry, 210 (111125). ISSN 0162-0134

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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)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.

Item Type:	Article
Additional Information:	0162-0134/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). Cite as: Awatif Rashed Z. Almotairy, Diego Montagner, Liam Morrison, Michael Devereux, Orla Howe, Andrea Erxleben, Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells, Journal of Inorganic Biochemistry, Volume 210, 2020, 111125, ISSN 0162-0134, https://doi.org/10.1016/j.jinorgbio.2020.111125. (https://www.sciencedirect.com/science/article/pii/S0162013420301537)
Keywords:	Platinum(IV) complexes; Histone deacetylase inhibitor; Cytotoxicity; DNA damage; Apoptosis; Reactive oxygen species;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	14741
Identification Number:	https://doi.org/10.1016/j.jinorgbio.2020.111125
Depositing User:	Diego Montagner
Date Deposited:	02 Sep 2021 16:31
Journal or Publication Title:	Journal of Inorganic Biochemistry
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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