When Will Small Molecule Lactate Dehydrogenase Inhibitors Realize Their Potential in the Cancer Clinic?

Abstract

Keywords: cancer metabolism • drug discovery • hLDH5 inhibitors • tumor glycolysis • Warburg effectReaching beyond the success in development of anticancer drugs meant to precisely focus first on one hallmark of cancer and the production of a novel type of small molecules that are selective and specific for cancer treatment. Safety is a major challenge than the efficacy in the drug development processes of small molecules, for both the academic research and pharmaceutical industries. From a metabolic assessment, unlike normal cells, the most characteristic feature of cancer cells is an unusual metabolic profile exhibiting a high rate of glucose consumption and lactate production due to increased glycolytic activity to supply them sufficient energy and metabolites. This phenomenon, known as the 'Warburg effect' described the fact that the metabolic shift toward aerobic glycolysis is largely accepted as a key metabolic hallmark of cancer cells [1]. This metabolic alteration is independent of the availability of oxygen, resulting in increased levels of lactate and lower ATP production. Additionally, this metabolic trait provides a selective advantage for cancer cells to grow and proliferate and to support biomass synthesis even in the hypoxic environment. In fact, the 'glucose addiction' of cancer cells is considered to be an Achilles heel of cancer because of the highly susceptible nature of cancer cells to glucose withdrawal [2,3]. Is human lactate dehydrogenase-5 an innovative anticancer target?Recently, researchers from both academia and industries, have renewed interest in development of anticancer drugs by targeting human lactate dehydrogenase-5 (hLDH-5) and to explore the role of hLDH-5 in cancer initiation, growth and maintenance and its utility as a tumor biomarker. hLDH-5 enzyme occupies a crucial position in the Warburg effect and catalyzes the reduction of pyruvate coupled with the oxidation of nicotinamide adenine dinucleotide dehydrogenase (NADH) to form lactate and NAD (+) at the end in the final step of the glycolytic pathway. The NAD (+) thus obtained to determine the continuity of glycolysis [4]. Till date, the hLDH-5 isoform received a position in the list of highly promising hallmark of cancer, in other words, highly promising targets for cancer drug development and cancer treatment due to following main crucial facts such as: hLDH-5 isoform holds significant role as a metabolic checkpoint in the cancer glycolytic pathway; associations of this enzyme with the activation of some proto-oncogenes; its link with the maintenance of invasiveness and metastatic potential; and finally connection of hLDH-5 isoform to chemoresistance of cancer cells [5,6]. Is hLDH-5 a safe target?In our point of view, hLDH-5 isoform has significant functional roles in the development and survival of wide range of human cancers; thus, the total LDH activity and LDH isoform patterns could be utilized for diagnostic and prognostic significance and in neoplastic diseases. Kanno et al. found that the probable side effect mig...

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Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil

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