Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma

摘要: Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse recalcitrant disease. This challenge has fostered the development novel approaches to treatment, including antagonists 'inhibitor apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus inhibitor (IZ) treatment selectively induced tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines patient xenografts. The induction necroptosis was common in ovarian cancer, expression catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, fact sufficient compromise survival RIPK3-negative, necroptosis-resistant cells. formation necrosome-like complex second critical effector, serine-threonine kinase-1 (RIPK1), observed. RIPK1, RIPK3 TNFα were required that inhibit function any these targets prevented death. Abundant transcript serous cancers, suggesting further evaluation targeting this RIPK3-dependent pathway may be clinical benefit.