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Abstract #0811

Effect of lonidamine on response to temozolomide in a human glioma model

Kavindra Nath1, Jeffrey Roman1, Lili Guo1, David Nelson1, Mary Putt1, Stepan Orlovskiy1, Ewere Azagidi1, Violet Tu1, Dennis Leeper2, Marco Paggi3, Yancey Gallespie4, Corinne Griguer4, Ian Blair1, and Jerry Glickson1

1University of Pennsylvania, Philadelphia, PA, United States, 2Thomas Jefferson University, Philadelphia, PA, United States, 3Regina Elena National Cancer Institute, IRCCS, Rome, Italy, 4University of Alabama, Birmingham, AL, United States

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 (╬▓NTP/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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