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首页> 外文期刊>Oncogene >BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma
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BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma

机译：BH3拟肽能有效激活细胞凋亡并在神经母细胞瘤中显示出单药功效

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The major impediment to cure for many malignancies is the development of therapy resistance with resultant tumor progression. Genetic alterations leading to subversion of inherent apoptosis pathways are common themes in therapy resistance. Bcl-2 family proteins play a critical role in regulating mitochondrial apoptosis that governs chemotherapeutic effects, and defective engagement of these pathways contributes to treatment failure. We have studied the efficacy of BH3 peptidomimetics consisting of the minimal death, or BH3, domains of the proapoptotic BH3-only proteins Bid and Bad to induce apoptosis using neuroblastoma (NB) as a model system. We demonstrate that BH3 peptides, modified with an arginine homopolymer for membrane transduction (called r8-BidBH3 and r8-BadBH3, respectively), potently induce apoptosis in NB cells, including those with MYCN amplification. Cell death is caspase 9 dependent, consistent with a requirement for the intrinsic mitochondrial pathway. Substitutions at highly conserved residues within the r8-BidBH3 peptide abolish apoptotic efficacy supporting activity through specific BH domain interactions. Concomitant exposure to r8-BadBH3 and r8-BidBH3 at sublethal monotherapy doses revealed potent synergy consistent with a competitive displacement model, whereby BH3 peptides displace sequestered BH3 proteins to induce cell death. Further, BH3 peptides demonstrate antitumor efficacy in a xenograft model of NB in the absence of additional genotoxic or trophic stressors. These data provide proof of principle that targeted re-engagement of apoptosis pathways may be of therapeutic utility, and BH3-like compounds are attractive lead agents to re-establish therapy-induced apoptosis in refractory malignancies.
机译：治愈许多恶性肿瘤的主要障碍是治疗抵抗的发展以及随之而来的肿瘤进展。导致固有凋亡途径颠覆的遗传改变是治疗耐药性的常见主题。 Bcl-2家族蛋白在调节线粒体凋亡中起着至关重要的作用，而线粒体凋亡控制着化学疗法的作用，这些途径的缺陷结合导致治疗失败。我们研究了使用神经母细胞瘤（NB）作为模型系统，由促凋亡的仅BH3蛋白Bid和Bad的最小死亡或BH3结构域组成的BH3拟肽的功效。我们证明，用精氨酸均聚物修饰的BH3肽可进行膜转导（分别称为r8-BidBH3和r8-BadBH3），可有效诱导NB细胞凋亡，包括那些具有MYCN扩增的细胞。细胞死亡是caspase 9依赖性的，与内在线粒体途径的要求一致。 r8-BidBH3肽内高度保守残基的取代取消了通过特定BH结构域相互作用而支持活性的凋亡功效。亚致死性单药治疗剂量同时暴露于r8-BadBH3和r8-BidBH3揭示了与竞争性置换模型一致的有效协同作用，其中BH3肽置换了螯合的BH3蛋白以诱导细胞死亡。此外，在没有其他遗传毒性或营养应激因子的情况下，BH3肽在NB的异种移植模型中显示出抗肿瘤功效。这些数据提供了原理性证据，表明凋亡通路的靶向重新接合可能具有治疗作用，并且BH3样化合物是在难治性恶性肿瘤中重建治疗诱导的凋亡的诱人先导剂。

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