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首页> 外文期刊>Cancer biology & therapy >Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists.
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Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists.

机译：Mcl1下调使神经母细胞瘤对细胞毒性化疗和小分子Bcl2家族拮抗剂敏感。

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Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.
机译：神经母细胞瘤（NB）是一种常见的高度致死性小儿癌症，治疗失败很大程度上归因于化学抗药性的出现。生存前的Bcl2同源性（BH）蛋白关键地调节细胞凋亡，并且可能代表着恢复NB中药物敏感性的重要治疗靶标。我们使用人类NB肿瘤组织微阵列来调查生存前BH蛋白Mcl1和Bcl2的表达，并将其与临床预后因素和生存相关联。原发性NB肿瘤异质表达Mcl1或Bcl2，高表达与高风险表型相关。共表达很少（11％），但与存活率降低相关。使用RNA干扰，我们调查了Mcl1和Bcl2在高风险NB细胞系（SK-N-AS，IMR-5，NLF）中的功能相关性。 Mcl1击倒诱导所有NB细胞系的凋亡，而Bcl2击倒仅抑制NLF，表明功能异质性。最后，我们确定了Mcl1与常规化学疗法（依托泊苷，阿霉素）和小分子Bcl2家族拮抗剂（ABT-737和AT-101）的抗药性相关。 Mcl1沉默对化学疗法的敏感性提高了2到300倍，而Bcl2沉默则没有，即使在对Bcl2敏感的NLF细胞中也是如此。靶向Bcl2 / -w / -x的对ABT-737的抗性已通过Mcl1敲低得以克服。 AT-101也可中和Mcl1，具有单药细胞毒性，而Mcl1敲低会进一步增强这种毒性。总之，Mcl1似乎是一种主要的促生存蛋白，可促进NB的化学耐药性，而Mcl1的失活可能代表了一种新的治疗策略。具有更高的Mcl1亲和力的化合物的优化，或与其他Mcl1拮抗剂的组合，可增强该方法的临床实用性。

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