Sensitization of cancer cells to TRAIL-induced apoptosis by drugs targeting mitochondrial ROS and endoplasmic reticulum

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promising for cancer treatment because of its selective cytotoxicity toward tumor cells. However, some cancer cell types including malignant melanoma are resistant to the TRAIL-mediated cytotoxicity. Therefore, drugs that potentiate TRAIL effectiveness are urgently required. A variety of agents such as inhibitors of proteases, histone deacetylases, and tyrosine kinases modulate different processes in the extrinsic or intrinsic (mitochondrial) death pathways and therefore give potential strategies to re-sensitize tumor cells to TRAIL. A growing body of evidence suggests that the endoplasmic reticulum (ER) is the key player in regulation of apoptosis and that ER stress is the major cause of a variety of pro-apoptotic effects. We recently discovered that divergent agents, including ATP-sensitive potassium (KATP) channel inhibitors, hydrogen peroxide (H2O2), the garlic organosulfur compound diallyl trisulfide and the mitochondrial fission inhibitor Mdivi-1, commonly potentiated the TRAIL-induced apoptosis in human leukemia, melanoma, and/or non-small cell lung cancer cells. These agents also potentiated apoptosis induced by agonistic monoclonal antibodies against death receptor 4 and 5. At higher concentrations, these agents alone had substantial apoptosis-inducing activities. Importantly, these agents spared normal cells such as melanocytes and fibroblasts, indicating that their effects are tumor-selective. Our data suggest that (i) these agents commonly induce mitochondrial reactive oxygen species (ROS) generation. (ii) The mitochondrial ROS trigger an ER-mediated death pathway involving X-box-binding protein-1 and caspase-12, which is important for re-sensitizing tumor cells to TRAIL. (iii) Normal cells are more resistant than tumor cells to the TRAIL-induced mitochondrial ROS generation. Based on our findings and others, the new strategies to overcome TRAIL resistance by agents targeting the mitochondria-ER dynamics will be discussed.