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.

广泛研究了表观遗传学试剂（例如组蛋白脱乙酰基酶（HDAC）抑制剂）用于联合抗癌治疗，Pt药物与HDAC抑制剂的共同给药已显示出治疗耐药性癌症的希望。通过将HDAC抑制剂与顺铂Pt（IV）衍生物的轴向位置进行配位，可以将表观遗传药物和Pt化疗药物合并为一个分子。在这项工作中，我们使用HDAC抑制剂4-苯基丁酸酯（PBA）和已知的Pt（IV）络合物顺，顺，反-[Pt（NH ₃）₂ Cl ₂（PBA）₂ ]（B）进行了机理研究。其衍生物顺式，顺式，反式-[Pt（NH ₃）₂ Cl ₂（PBA）（OH）]（A），顺式，顺式，反式-[Pt（NH ₃）₂ Cl ₂（PBA）（Bz）]（C） ，和顺式，顺式，反式- [铂（NH ₃）₂氯₂（PBA）（的Suc）]（d）（Bz =苯甲酸酯，Suc =琥珀酸酯）。比较顺铂敏感性和顺铂耐药性卵巢癌细胞的细胞毒性，对HDAC活性的影响，活性氧（ROS）生成，γ-H2AX（组蛋白2A家族成员X）灶的生成和凋亡的诱导，结果表明，A – C表现出涉及DNA损伤和细胞凋亡的多峰机制，独立于顺铂耐药性。