Tumor Selective Apoptosis by TRAIL

C-FLIP是一种关键的抗凋亡因子，在许多肿瘤中过表达，并通过干扰FADD、caspase-8和DR5来阻断凋亡机制。大量证据表明，c-flip在肿瘤中的过度表达是抵抗TRAIL诱导的细胞凋亡的主要原因。因此，抑制c-flip作用和克服c-flip诱导的肿瘤细胞耐药性的策略可能会带来新的和更有效的治疗方法。我们已经发现了一种生物活性多肽ApoFLIP，它可以与c-Flip拮抗，并恢复c-Flip表达细胞的凋亡机制。这项提案的主要目标是开发和鉴定这种多肽的药物样变异体。这些药物可以为血液系统恶性肿瘤和其他对凋亡诱导疗法表现出抵抗力的肿瘤的当前治疗策略提供显著的增强。

c-FLIP is a key anti-apoptotic factor that is over-expressed in many tumors and blocks the apoptotic machinery by interfering with FADD, caspase-8 and DR5. Significant evidence demonstrates that c-FLIP over-expression in tumors is a major cause of resistance to TRAIL-induced apoptosis. Therefore, strategies to inhibit c-FLIP action and to overcome c-FLIP-induced resistance in tumor cells may lead to novel and more effective therapies. We have discovered a bioactive peptide, ApoFLIP that antagonizes with c-FLIP and reinstates the apoptotic machinery in c-FLIP expressing cells. The major goal of this proposal is to develop and characterize drug-like variants of this peptide. These agents could provide significant enhancements in the current therapeutic strategies in hematological malignancies and other tumors that show resistance to apoptosis-inducing therapeutics.