Novel Pt(IV) complexes to overcome multidrug resistance in gastric cancer by targeting P‐glycoprotein

Abstract Systematic toxicity and drug resistance significantly limited FDA-approved platinum drugs for further clinical applications. In order to reverse the resistance (MDR) and enhance their anticancer efficiency, four Pt(IV) complexes (12-15) conjugating with P‐glycoprotein (P-gp) inhibitors were designed and synthesized. Among them, complex 14 (IC50 =3.37 μM) efficiently reversed cisplatin resistance in SGC-7901/CDDP cell line and increased selectivity index (6.9) against normal HL-7702 cell line. Detailed mechanisms in SGC-7901/CDDP cells assays revealed that complex 14 efficiently induced apoptosis via down-regulating expression of P-gp for enhanced intracellular uptake of platinum, arrested cells at G2/M phase, induced DNA damage and initiated mitochondrial apoptosis pathway. Further in vivo studies demonstrated that the enhanced accumulation of complex 14 contributed to tumor inhibition of 75.6 % in SGC-7901/CDDP xenografts, which was much higher than cisplatin (25.9 %) and oxaliplatin (43 %). Moreover, the low systematic toxicity made 14 a potential novel P-gp-mediated MDR modulator.