Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner.

摘要: Second mitochondria-derived activator of caspase (Smac) is a mitochondrial protein released into the cytosol during apoptosis. Smac mimetics have recently been touted as novel therapeutic to induce apoptosis in cancer cells. The ability vitro has shown be dependent upon both XIAP neutralization and cell autocrine tumor necrosis factor-α (TNF-α) production. In this study we provide new evidence for utility combination with conventional chemotherapy agents exacerbate activation death. Furthermore, find that effect because multifaceted mechanism involving inhibition proliferation by an enhanced TNF-α feedback loop mimetic/chemotherapy agent combination. Surprisingly, although genotoxic typically through intrinsic pathway, show synergism mediated TNF-α/RIP1-dependent leading extrinsic apoptotic pathway. Finally, report contributes mimetic-induced regression single or chemotherapeutics xenograft mouse models. Collectively, mechanistic applicable data support translational studies use antineoplasm modality.