Novel Indole–Chalcone Derivative-Ligated Platinum(IV) Prodrugs Attenuate Cisplatin Resistance in Lung Cancer through ROS/ER Stress and Mitochondrial Dysfunction

Abstract

Developing multifunctional platinum(IV) prodrugs via integrating bioactive pharmacophores into one entity is an attractive strategy to ameliorate the defects of platinum(II) drugs. Herein, a series of indole-chalcone derivative-ligated platinum(IV) complexes were synthesized and evaluated for their anticancer activities. Among them, optimal complex <b>17a</b> exerted superior activity compared to that of cisplatin (CDDP) against the tested cells but showed lower cytotoxicity toward human normal lung cells. Detailed mechanisms demonstrated that <b>17a</b> significantly enhanced intracellular accumulation, induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, <b>17a</b> efficiently disturbed the tubulin-microtubule system, initiated reactive oxygen species (ROS)-mediated endoplasmic reticulum stress, and activated a mitochondrion-dependent apoptosis signaling pathway. Besides, <b>17a</b> was superior to free drugs or their combination in inhibiting cancer growth in A549/CDDP xenografts without inducing obvious side effects. The physical mixture of <b>16a</b> and CDDP was almost identical to <b>17a</b> but showed apparent systematic side effects. In summary, our studies may provide an efficient treatment regimen for CDDP resistance.