Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
Bottom Line: However, the effect of LND on central energy metabolism has never been fully characterized.The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation.Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate.
Affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.Show MeSH
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Mentions: To examine the effect of LND on melanoma cell metabolism, we used LC-selected reaction monitoring/MS to analyze the metabolites in DB-1 melanoma cells treated with LND. As a monocarboxylate transporter inhibitor, LND is known to stimulate lactate accumulation in cells (25, 26). After 1 h of treatment with 150 μm LND, lactate was elevated nearly 5-fold over control cells (Fig. 1A). The levels of succinate and α-ketoglutarate in LND-treated DB-1 cells were found to increase, whereas the levels of citrate, fumarate, and malate decreased (Fig. 1, B and C). A 3–5-fold accumulation of succinate was also observed in a variety of cancer cell lines, including HepG2 (Fig. 1D), HCT116 (Fig. 1E), and HeLa (Fig. 1F).
Affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.