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

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 17a 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 17a significantly enhanced intracellular accumulation,
induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, 17a efficiently disturbed the tubulin–microtubule system,
initiated reactive oxygen species (ROS)-mediated endoplasmic reticulum
stress, and activated a mitochondrion-dependent apoptosis signaling
pathway. Besides, 17a 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 16a and CDDP was almost identical to 17a but showed apparent
systematic side effects. In summary, our studies may provide an efficient
treatment regimen for CDDP resistance.