On-target Inhibition of Tumor Fermentative Glycolysis as Visualized by Hyperpolarized Pyruvate
On-target Inhibition of Tumor Fermentative Glycolysis as Visualized by Hyperpolarized Pyruvate
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DOI：
10.1593/neo.101020
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发表时间：
2011-01-01
期刊：
影响因子：
4.8
通讯作者：
Sukhatme, Vikas P.
中科院分区：
文献类型：
--
作者：
Seth, Pankaj;Grant, Aaron;Sukhatme, Vikas P.
许多癌细胞表现出瓦尔堡效应，即糖酵解增强，然后发酵（丙酮酸转化为乳酸）。最近，这些作用的分子基础已经开始阐明，并且乳酸脱氢酶的乳酸脱氢酶A（LDH-A）同种型的上调被认为是这种现象的主要分子介体。此外，肿瘤组织中的LDH-A表达和血液中的LDH-A水平预示着不良预后，并且LDH-A阻断可导致肿瘤移植模型中的肿瘤生长抑制。我们扩展了现有的数据（其中一些是在我们进行研究期间发表的）主要有两个方面：1）糖酵解肺癌细胞系中LDH-A的抑制导致活性氧介导的细胞凋亡和对化疗药物紫杉醇的敏感性增加，和2）发酵糖酵解的抑制也可以通过药物二氯乙酸激活丙酮酸脱氢酶复合物来实现，目前正在进行临床试验，并且该现象可以通过使用超极化丙酮酸的磁共振光谱以非侵入性实时方式在体内监测。总的来说，这些数据表明，可以通过使用超极化磁共振波谱法（一种可扩展到人类使用的方法）监测药物的体内作用，该药物重定向丙酮酸盐的命运，因此旨在逆转瓦尔堡效应。
Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentation (conversion of pyruvate to lactate). Recently, the molecular basis for these effects has started to be elucidated, and the up-regulation of the lactate dehydrogenase A (LDH-A) isoform of lactate dehydrogenase is felt to be a major molecular mediator of this phenomenon. Moreover, LDH-A expression in tumor tissue and LDH-A levels in blood portend a bad prognosis, and LDH-A blockade can lead to tumor growth inhibition in tumor transplant models. We have extended existing data (some of which were published during the time when we were carrying out our studies) in two important ways: 1) inhibition of LDH-A in a glycolytic lung cancer cell line results in reactive oxygen species-mediated apoptosis and increased sensitivity to the chemotherapeutic drug paclitaxel and 2) inhibition of fermentative glycolysis can also be accomplished by activation of the pyruvate dehydrogenase complex by the drug dichloroacetate, now undergoing clinical trials, and that this phenomenon can be monitored in vivo in a noninvasive real-time manner through magnetic resonance spectroscopy using hyperpolarized pyruvate. Collectively, these data suggest that in vivo effects of drugs that redirect the fate of pyruvate, and hence are aimed at reversing the Warburg effect, could be monitored through the use of hyperpolarized magnetic resonance spectroscopy, a method that is scalable to human use.