Dual–target platinum(IV) complexes reverse cisplatin resistance in triple negative breast via inhibiting poly(ADP–ribose) polymerase (PARP–1) and enhancing DNA damage

Abstract

Platinum(II)–based drugs play an important role in many chemotherapeutic protocols, but their further clinical applications are hindered by the development of drug resistance and serious side effects. Therefore, to reverse cisplatin (CDDP) resistance in tandem with reduced side effects, nine novel platinum(IV) complexes modified with key pharmacophore of Olaparib were synthesized and evaluated for biological activities. Among them, the optimal complex 8–2 showed good inhibitory activity against PARP–1 and superior anticancer effects over CDDP on parental (MDA–MB–231, IC50 = 1.13 μM) and CDDP –resistant triple–negative breast cancer (TNBC) cell line (MDA–MB–231/CDDP, IC50 = 1.72 μM). Detailed mechanisms revealed that compared with Olaparib and CDDP, the enhanced intracellular accumulation of 8–2 could efficiently reverse CDDP resistance in MDA–MB–231/CDDP cells via inhibiting DNA repair–associated mechanisms, enhancing DNA damage, and activating mitochondrion–dependent apoptosis pathway. Furthermore, 8–2 obtained higher tumor growth inhibition rate (64.1 %) than CDDP (26.5 %) in MDA–MB–231/CDDP xenografts, but it did not induce significant toxicity in vivo and in intro, making it a potential drug candidate for the treatment of TNBC.