Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression
Due to genetic alterations and tumor hypoxia, many cancer cells exhibit high glucose uptake and lactate production through lactate dehydrogenase A (LDHA), which is regulated by c-Myc and hypoxia-inducible factor (HIF-1). While previous studies have suggested that LDHA plays a role in tumor initiation, its involvement in tumor maintenance and progression remains unclear. Additionally, the mechanisms by which reducing LDHA expression through interference or antisense RNA inhibits tumorigenesis are not well understood. In this study, we demonstrate that silencing LDHA with siRNA or inhibiting it using the small-molecule inhibitor FX11 (3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid) leads to reduced ATP levels, significant oxidative stress, and cell death, which can be partially reversed by the antioxidant N-acetylcysteine. We also show that FX11 inhibits the progression of large human lymphoma and pancreatic cancer xenografts. When combined with the NAD(+) synthesis inhibitor FK866, FX11 induces lymphoma regression. These findings suggest that targeting LDHA with FX11 is a feasible and tolerable treatment strategy for LDHA-dependent tumors. Our study highlights a therapeutic approach targeting the Warburg effect and underscores the importance of oxidative stress and metabolic profiling in cancer biology for the therapeutic targeting of cancer energy metabolism.