Mechanism of vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug resistance in lung cancer

Abstract

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 (IC50 = 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.