Design of a novel Pt(II) complex to reverse cisplatin-induced resistance in lung cancer via a multi-mechanism

In order to develop a novel platinum (Pt) complex aiming to overcome cisplatin resistance, we synthesised a series of novel Pt complexes (C1-C6). These Pt complexes displayed potent cytotoxicity activity against resistant lung cancer cells (A549cisR) in vitro and efficiently inhibited tumour growth in vivo. The Pt complexes can target DNA, lead to DNA platination and cause cell cycle arrest in the S phase, thus impeding precise DNA synthesis. C6, in particular, induced not only apoptosis but also lethal autophagy in A549cisR cells. In addition, these novel Pt complexes reversed cisplatin-induced resistance via inhibiting the expression of P-glycoprotein and decreasing the level of glutathione in A549cisR cells. Moreover, the ERK pathway was involved in C6-induced overcoming cisplatin resistance.