Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

Abstract

In the attempt of developing innovative anticancer treatments, growing interest has recently focused on the peculiar metabolic properties of cancer cells. In this context, LDH, which converts pyruvate to lactate at the end of glycolysis, is emerging as one of the most interesting molecular targets for the development of new inhibitors. In fact, because LDH activity is not needed for pyruvate metabolism through the TCA cycle, inhibitors of this enzyme should spare glucose metabolism of normal non-proliferating cells, which usually completely degrade the glucose molecule to CO2. This review is aimed at summarizing the available data on LDH biology in normal and neoplastic cells, which support the anticancer therapeutic approach based on LDH inhibition. These data encouraged pharmaceutical industries and academic institutions in the search of small-molecule inhibitors and promising candidates have recently been identified. The availability of inhibitors with drug-like properties will allow the evaluation in the near future of the real potential of LDH inhibition in anticancer treatment, also making the identification of the most responsive neoplastic conditions possible.

Breaking Cryo-EM Resolution Barriers to Facilitate Drug Discovery

“…However, in cancer cells, irrespective of oxygen availability, glycolysis followed by production of lactate through LDH is the preferred pathway, enhancing the production of metabolic precursors required for biosynthesis of cellular macromolecules. The recognition in a growing number of cancers of the central role of both LDH A and B isoforms (Fiume et al, 2014; McCleland et al, 2013; Rodriguez et al, 2003) has driven the identification of small-molecule inhibitors, including mercaptocyclohex-2-enone derivatives that bind away from the NAD-binding pocket and are not competitive inhibitors (Dragovich et al, 2014), as well as sulfamoylquinoline benzoic acid derivatives, which compete with NAD binding to LDH (Billiard et al, 2013). To evaluate the potential of cryo-EM to determine structures of a small protein complex such as LDH and localize the binding sites of potential small-molecule inhibitors, we carried out cryo-EM analysis of LDH B in complex with GSK2837808A, a 650 Dalton compound in the quinoline 3-sulfonamide series (Billiard et al, 2013).…”

Therapeutic targeting of cellular stress responses in cancer

“…AMPK, HIFα, PGC1α), providing a wide variety of options for pharmaceutical targeting . For example, in the case of MYC‐induced metabolic stress, inhibitors of glutaminase and lactate dehydrogenase have been shown to suppress tumor growth by blocking the flux of the nutrients required for cancer cell proliferation in response to upregulated MYC activity . Similarly, manipulating the response pathways involved in adaptation to MYC‐induced metabolic stress has been also considered as a therapeutic option.…”

Phenylpropanoids and flavonoids from Phlomis kurdica as inhibitors of human lactate dehydrogenase

“…In particular, the A-subunit of LDH (LDH-A), which exclusively generates h LDH5 in its fully functional tetrameric form, catalyzes a crucial step in glycolysis, the reduction of pyruvate to lactate. Therefore, inhibition of LDH may be considered a promising strategy in cancer treatment, since it should cause a starvation of cancerous cells by reducing their conversion of glucose to lactate (Fiume et al, 2014). So far, several small molecules displaying efficient LDH inhibitory potencies have been reported, and they are generally characterized by the presence of carboxylates and/or phenolic OH groups in their structures (Granchi et al, 2013).…”