Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
J Clin Invest. 2010 Jan;120(1):142-56. doi: 10.1172/JCI38942. Epub 2009 Dec 21.
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.
传统观点认为，癌细胞主要通过糖酵解产生 ATP，而不是通过氧化供能底物。最近在白血病细胞中发现，线粒体解偶联——在没有合成 ATP 的情况下持续减少氧气——可以绕过氧气抑制糖酵解的能力，并通过从丙酮酸氧化转向脂肪酸氧化 (FAO) 来促进对糖酵解的代谢偏好。在这里，我们已经证明，用 etomoxir 或 ranolazine 抑制 FAO 的药理作用，可抑制人白血病细胞（单独培养或在骨髓基质细胞上培养）的增殖，并使其对 ABT-737 诱导的细胞凋亡敏感，ABT-737 是一种能将促凋亡 Bcl-2 蛋白（如 Bak）从抗凋亡家族成员中释放出来的分子。同样，用脂肪酸合酶/脂肪水解抑制剂奥利司他处理也能使白血病细胞对 ABT-737 敏感，这支持了脂肪酸促进细胞存活的观点。从机制上讲，我们提供了证据表明 FAO 调节 Bak 依赖性线粒体通透性转换的活性。重要的是，etomoxir 使大约 50%的原发性人急性髓性白血病样本中的静止白血病祖细胞数量减少，并且当与 ABT-737 或阿糖胞苷联合使用时，在白血病的小鼠模型中提供了显著的治疗益处。这些结果支持了 FAO 抑制剂作为血液恶性肿瘤治疗策略的概念。
