L lactate dehydrogenase drives cancer metabolism and offers new therapeutic opportunities

Abstract

Lactate dehydrogenase (LDH) plays a crucial role in cancer diagnosis and treatment. Previously, LDH was associated with the “Warburg effect,” and lactate was considered a mere “waste product” from anaerobic respiration. This review adopts the modern understanding of lactate as an essential “fuel,” not a waste product. We explain in detail the new mechanism, known as the mitochondrial lactate shuttle (ml-LDH). This understanding reveals that a version of (mL-LDH) and a monocarboxylate Transporter (MCT1) reside within the mitochondria. Transport lactate formed in the cytoplasm and convert it back to pyruvate, which is directly imported into the Krebs cycle (TCA cycle). This new understanding of the perspective on cancer shifts it from a simple “Warburg effect” to a “metabolic symbiosis” model within the tumor. In this model, LDHA (in the cytoplasm) “synthesizes” lactate, and LDHB (in the mitochondria) “consumes” this lactate as fuel for growth. So, LDH is a “prognostic marker” for cancer, and targeting LDHA has become an important therapeutic strategy. The inhibitors, such as oxamates and FX11, as well as their limitations, are also discussed. Nanotechnology, specifically a material called “Layered Double Hydroxides”, acts as a nanocarrier for drug delivery or miRNAs (such as miR-30a) to cancer cells. Green biomaterials, such as copper nanoparticles (Cu-NPs), have been shown to inhibit LDH enzyme activity. This review provides a comprehensive and up-to-date overview of the enzyme’s role, resolving inconsistencies between older and modern understandings of lactate metabolism, and exploring the latest nano-therapy strategies as a future challenge in cancer therapy.