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

Awatif Rashed Z Almotairy,Orla Howe,Michael Devereux,Andrea Erxleben,Liam Morrison,Diego Montagner

doi:10.1016/j.jinorgbio.2020.111125

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.

Highlights

Cisplatin (cis-[Pt(NH3)2Cl2]) has been used as a chemotherapeutic cancer drug since 1978, in the treatment of testicular, head and neck, bladder and ovarian carcinomas [1]
A2780 and A2780cis ovarian cancer cells than cisplatin and induce cell death pathways leading to apoptosis in both cell lines
While our study confirms that the three Pt(IV) complexes interact with their intended targets, DNA and histone deacetylase (HDAC), it has to be kept in mind that their mode(s) of action may be more complex

Summary

Introduction

Cisplatin (cis-[Pt(NH3)2Cl2]) has been used as a chemotherapeutic cancer drug since 1978, in the treatment of testicular, head and neck, bladder and ovarian carcinomas [1]. The generally accepted mode of action of cisplatin involves covalent binding of the cis-Pt (NH3)22+ entity to adjacent guanine bases in DNA following loss of the chlorido leaving group ligands. The formation of these DNA lesions triggers the DNA damage response by activating or silencing various genes. The main types of epigenetic alterations in general are DNA methylation and histone methylation or acetylation [6]. Histone acetylation has a critical regulatory function in DNA repair and recent studies suggest that it plays a role in the development of drug resistance [4]. Histone acetylation and deacetylation are catalyzed by histone acetyltransferase (HAT) and histone deacetylase (HDAC) respectively

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Results

Conclusion