Lactate and malignant tumors: a therapeutic target at the end stage of glycolysis.
Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors. Primarily the result of altered isozyme expression, these adaptations enhance the survival and proliferation of the tumor at the expense of surrounding normal tissue. Consequently, they also expose a unique set of targets for tumor destruction while sparing healthy tissues. Despite this fact, development of drugs to directly target such altered metabolic pathways of malignant tumors has been under-investigated until recently. One such target is the ultimate step of glycolysis, which, as expected, presents itself as a metabolic aberration in most malignant tumors. Termed "aerobic glycolysis" due to abnormal conversion of pyruvic acid to lactic acid even under normoxia, the altered metabolism requires these tumors to rapidly efflux lactic acid to the microenvironment in order to prevent poisoning themselves. Thus, exposed is a prime "choke-point" to target these highly malignant, frequently chemo- and radio- resistant tumors. This review will focus on current outcomes in targeting lactate efflux in such tumors using glioma as a model, an ongoing project in our laboratory for the past half-decade, as well as supporting evidence from recent studies by others on targeting this "tail-end" of glycolysis in other tumor models.
Mathupala
Saroj P
SP
Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, 808 HWCRC, 4100 John R. Road, Detroit, MI 48201, USA. smathupala@med.wayne.edu
Colen
Chaim B
CB
Parajuli
Prahlad
P
Sloan
Andrew E
AE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019344:Lactic Acid / Q000096:biosynthesis; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*
D000970:Antineoplastic Agents; D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid; D019289:Pyruvic Acid; D007770:L-Lactate Dehydrogenase