Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway

Abstract

In search for novel strategies in colon cancer treatment, we investigated the unique ability of platinum(IV) complex LA-12 to efficiently enhance the killing effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), and compared it with the sensitizing action of cisplatin. We provide the first evidence that LA-12 primes human colon cancer cells for TRAIL-induced cytotoxicity by p53-independent activation of the mitochondrial apoptotic pathway. The cooperative action of LA-12 and TRAIL was associated with stimulation of Bax/Bak activation, drop of mitochondrial membrane potential, caspase-9 activation, and a shift of the balance among Bcl-2 family proteins in favor of the pro-apoptotic members. In contrast to cisplatin, LA-12 was a potent inducer of ERK-mediated Noxa and BimL protein upregulation, and more effectively enhanced TRAIL-induced apoptosis in the absence of Bax. The cooperative action of LA-12 and TRAIL was augmented following the siRNA-mediated silencing of Mcl-1 in both Bax proficient/deficient cells. We newly demonstrated that LA-12 induced ERK-mediated c-Myc upregulation, and proved that c-Myc silencing inhibited the mitochondrial activation and apoptosis in colon cancer cells treated with LA-12 and TRAIL. The LA-12-mediated sensitization to TRAIL-induced apoptosis was demonstrated in several colon cancer cell lines, further underscoring the general relevance of our findings. The selective action of LA-12 was documented by preferential priming of cancer but not normal colon cancer cells to TRAIL killing effects. Our work highlights the promising potential of LA-12 over cisplatin to enhance the colon cancer cell sensitivity to TRAIL-induced apoptosis, and provides new mechanistic insights into their cooperative action.