Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China; School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China.
Eur J Med Chem. 2022 Jul 5;237:114415. doi: 10.1016/j.ejmech.2022.114415. Epub 2022 Apr 26.
To overcome the resistance of tumour cells to cis-diaminedichloroplatinum(II) (cisplatin, DDP), we designed and synthesised platinum(II) complexes with copper coordination active sites using vitamin B6 and benzohydrazide derivatives as raw materials.The 3D structures of the complexes were confirmed by X-ray single-crystal diffraction. The results of the biological activity assay showed that the Pt(II) complexes (VB6-Pt1 and VB6-Pt2) have higher anti-tumour activity on detected typical lung cancer cells than DDP. Among them, VB6-Pt1 (IC = 0.78 μM) efficiently reversed DDP resistance in A549/DDP cell line and increased selectivity index (26) against mortal MRC-5 fibroblasts. The study showed that VB6-Pt1 overcomes tumor drug resistance by significantly increasing the level of reactive oxyge species and inducing lysosomal membrane permeability, which leads to mitochondrial dysfunction and cell apoptosis. Furthermore, the inhibitory effect of VB6-Pt1 on A549 xenograft tumours was 81.5%, which was much higher than that of cisplatin (50.0%), without significantly increasing p-glycoprotein (P-gp) protein expression. The copper-coordinated active site in Pt(II) complexes may be a key factor in their ability to overcome DDP-resistant cancer cells.
为了克服肿瘤细胞对顺二氨二氯铂(II)（顺铂，DDP）的耐药性，我们以维生素 B6 和苯甲酰肼衍生物为原料设计并合成了具有铜配位活性位点的铂(II)配合物。配合物的 3D 结构通过 X 射线单晶衍射得到证实。生物活性测定结果表明，Pt(II)配合物（VB6-Pt1 和 VB6-Pt2）对检测的典型肺癌细胞的抗肿瘤活性均高于 DDP。其中，VB6-Pt1（IC=0.78μM）能有效逆转 A549/DDP 细胞系对 DDP 的耐药性，并对致死性 MRC-5 成纤维细胞的选择性指数（26）增加。研究表明，VB6-Pt1 通过显著增加活性氧水平并诱导溶酶体膜通透性来克服肿瘤耐药性，导致线粒体功能障碍和细胞凋亡。此外，VB6-Pt1 对 A549 异种移植瘤的抑制作用为 81.5%，明显高于顺铂（50.0%），而对 P-糖蛋白（P-gp）蛋白表达的增加无明显影响。Pt(II)配合物中的铜配位活性位点可能是其克服 DDP 耐药癌细胞能力的关键因素。
