Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics

Abstract

Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.

Keywords: Cancer cell metabolism; LDH inhibitors; Lactate dehydrogenase A; Lactate shuttle; Tumor glycolysis.