Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction
Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction
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DOI：
10.1172/jci38942
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
--
作者：
Samudio, Ismael;Harmancey, Romain;Andreeff, Michael
传统观点认为，癌细胞主要通过糖酵解而不是通过氧化提供能量的底物来产生三磷酸腺苷。线粒体解偶联--在没有ATP合成的情况下，氧的持续减少--最近在白血病细胞中被证明可以绕过氧抑制糖酵解的能力，并可能通过从丙酮酸氧化转变为脂肪酸氧化(FAO)来促进对糖酵解的代谢偏好。在这里，我们已经证明了粮农组织与依托莫西或雷诺嗪的药理抑制抑制了增殖，并敏化了单独培养或在骨髓基质细胞上培养的人白血病细胞对ABT-737诱导凋亡的敏感性，ABT-737是一种从抗凋亡家族成员中释放促凋亡的Bcl-2蛋白的分子。同样，脂肪酸合成酶/脂解抑制剂奥利司他的治疗也使白血病细胞对ABT-737敏感，ABT-737支持脂肪酸促进细胞存活的概念。从机制上讲，我们产生的证据表明，FAO调节依赖于Bak的线粒体通透性转换的活性。重要的是，依托莫西减少了大约50%的原发人类中静止的白血病祖细胞的数量。在急性髓系白血病样本中，当与ABT-737或阿糖胞苷联合使用时，在小鼠白血病模型中提供了实质性的治疗益处。这一结果支持了粮农组织抑制剂作为血液系统恶性肿瘤治疗策略的概念。
The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling - the continuing reduction of oxygen without ATP synthesis - has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells - cultured alone or on bone marrow stromal cells - to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human. acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.