On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate.
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.
Department of Medicine, Divisions of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Pankaj
P
Seth
Aaron
A
Grant
Jian
J
Tang
Elena
E
Vinogradov
Xioaen
X
Wang
Robert
R
Lenkinski
Vikas P
VP
Sukhatme
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation; D006019:Glycolysis; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000080864:Lactate Dehydrogenase 5; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel
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