LDH isozymes as targets for cancer therapy

The Warburg effect, a hallmark of cancer, positions lactate dehydrogenase (LDH) as a key therapeutic target. Mammals possess three LDH isozymes (LDH-A, LDH-B, LDH-C) with distinct properties. This review critically re-evaluates the simplistic 'aerobic-anaerobic' paradigm, emphasizing that all isozymes catalyze reversible pyruvate-lactate conversion and contribute to tumor metabolism in a context-dependent manner. While LDH-A inhibition is a primary focus, challenges include metabolic plasticity and compensatory LDH-B upregulation. LDH-B plays a critical role in mitochondrial lactate oxidation. We highlight LDH-C as a compelling cancer/testis antigen target. Beyond glycolysis, LDH-C exhibits unique substrate promiscuity, generating oncometabolites like s-2-hydroxyglutarate from α-ketoglutarate. Its structural distinctions and restricted normal tissue expression offer opportunities for highly selective therapy. A comprehensive understanding of all three isozymes is essential for developing effective metabolic interventions against cancer.