The treatment of glioblastoma multiforme (GBM) includes temozolomide (TMZ) chemotherapy concurrent with radiotherapy. Lonidamine (LND), an inhibitor of monocarboxylate transporters 1&4, the mitochondrial pyruvate carrier, and complex II, is shown here to potentiate TMZ-induced growth inhibition of U251 glioma cells. Through LC-Mass Spectrometry of cells and 31P and 1H MRS of U251 xenografts, we identified mechanisms of this potentiation, including tumor-selective inhibition of bioenergetics (βNTP/Pi) and simultaneous acidification (intracellular pH and lactate) which may inhibit enzymes contributing to TMZ resistance such as glutathione-S-transferase and O6-methylguanine DNA methyltransferase (MGMT). LND may improve the current care of glioma patients and potentially overcome TMZ resistance.
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