NOXA as critical mediator for drug combinations in polychemotherapy.
NOXA as critical mediator for drug combinations in polychemotherapy.
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DOI：
10.1038/cddis.2012.53
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发表时间：
2012-06-21
影响因子：
9
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在综合化疗期间，细胞毒药物以组合方式给予，以增强其抗肿瘤效果。对于大多数药物组合来说，导致药物-药物相互作用的潜在信号机制仍然难以捉摸。在这里，我们证明了Bcl-2家族成员NOXA在某些药物组合中介导细胞死亡的决定性作用，即使单独给药时这些药物独立于NOXA起作用。在验证性研究中，白桦酸、阿霉素和长春新碱通过p53和noxa非依赖性途径诱导细胞死亡，包括线粒体孔形成、细胞色素c释放和caspase激活。相反，当白桦酸与多柔比星或长春新碱联合使用时，细胞死亡信号发生了显著变化；药物组合明显依赖于P53和NOXA。同样，在患者来源的急性白血病样本中，患者来源的细胞中的RNA干扰研究表明，在患者来源的急性白血病样本中，药物组合而不是单一药物依赖于P53和NOXA，这一点与此类似，具有很高的临床相关性。我们的数据强调，NOXA代表着一种重要的靶向分子，用于单独针对NOXA的药物组合。在多种化疗的复杂相互作用中，NOXA可能具有调节细胞凋亡敏感性的特殊作用。破译单一药物和药物组合在信号传递方面的差异，可能有助于设计高效的新型多药化疗方案。
During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug–drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens.