Department of BioSciences, Rice University, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cell Death Dis. 2019 Aug 13;10(8):617. doi: 10.1038/s41419-019-1851-3.
Mitochondria play a central and multifunctional role in the progression of tumorigenesis. Although many recent studies have demonstrated correlations between mitochondrial function and genetic makeup or originating tissue, it remains unclear why some cancers are more susceptible to mitocans (anticancer drugs that target mitochondrial function to mediate part or all of their effect). Moreover, fundamental questions of efficacy and mechanism of action in various tumor types stubbornly remain. Here we demonstrate that cancer type is a significant predictor of tumor response to mitocan treatment, and that acute myeloid leukemias (AML) show an increased sensitivity to these drugs. We determined that AML cells display particular defects in mitochondrial metabolism that underlie their sensitivity to mitocan treatment. Furthermore, we demonstrated that combinatorial treatment with a mitocan (CCCP) and a glycolytic inhibitor (2-deoxyglucose) has substantial synergy in AML cells, including primary cells from patients with AML. Our results show that mitocans, either alone or in combination with a glycolytic inhibitor, display anti-leukemia effects in doses much lower than needed to induce toxicity against normal blood cells, indicating that mitochondria may be an effective and selective therapeutic target.
线粒体在肿瘤发生的发展过程中起着核心和多功能的作用。尽管最近的许多研究已经证明了线粒体功能与遗传构成或起源组织之间的相关性，但仍不清楚为什么有些癌症更容易受到 mitocans（针对线粒体功能的抗癌药物，以介导其部分或全部作用）的影响。此外，在各种肿瘤类型中，关于疗效和作用机制的基本问题仍然存在。在这里，我们证明癌症类型是肿瘤对 mitocan 治疗反应的一个重要预测因子，并且急性髓系白血病（AML）对这些药物表现出更高的敏感性。我们确定 AML 细胞显示出线粒体代谢的特定缺陷，这是它们对 mitocan 治疗敏感的基础。此外，我们证明了 mitocan（CCCP）与糖酵解抑制剂（2-脱氧葡萄糖）联合治疗在 AML 细胞中具有显著的协同作用，包括来自 AML 患者的原代细胞。我们的结果表明，mitocans 无论是单独使用还是与糖酵解抑制剂联合使用，在诱导对正常血细胞毒性所需的剂量低得多的情况下，都显示出抗白血病作用，表明线粒体可能是一种有效和选择性的治疗靶点。
