Bonnet Sébastien, Archer Stephen L, Allalunis-Turner Joan, Haromy Alois, Beaulieu Christian, Thompson Richard, Lee Christopher T, Lopaschuk Gary D, Puttagunta Lakshmi, Bonnet Sandra, Harry Gwyneth, Hashimoto Kyoko, Porter Christopher J, Andrade Miguel A, Thebaud Bernard, Michelakis Evangelos D
Pulmonary Hypertension Program and Vascular Biology Group, Department of Physiology, University of Alberta, Edmonton, AB T6G 2B7, Canada.
Cancer Cell. 2007 Jan;11(1):37-51. doi: 10.1016/j.ccr.2006.10.020.
The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (DeltaPsim) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases DeltaPsim, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.
癌症独特的代谢特征（有氧糖酵解）可能赋予细胞抗凋亡能力，从而成为治疗靶点。与正常细胞相比，多种人类癌症具有较高的线粒体膜电位（ΔΨm）和较低的钾离子通道Kv1.5表达，这两者都有助于细胞产生抗凋亡能力。二氯乙酸（DCA）可抑制线粒体丙酮酸脱氢酶激酶（PDK），使代谢从糖酵解转变为葡萄糖氧化，降低ΔΨm，增加线粒体过氧化氢，并激活所有癌细胞而非正常细胞中的钾离子通道；DCA通过一种依赖NFAT1的机制上调Kv1.5。DCA可诱导细胞凋亡，减少细胞增殖，并抑制肿瘤生长，且无明显毒性。通过小干扰RNA对PDK2进行分子抑制可模拟DCA的作用。线粒体-NFAT-Kv轴和PDK是癌症治疗的重要靶点；口服可用的DCA是一种有前景的选择性抗癌药物。
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