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Mechanism of Action of the Antineoplastic Drug Lonidamine: ³¹P and ¹³C Nuclear Magnetic Resonance Studies

School of Chemistry, Tel-Aviv University, Tel Aviv, Israel [H. B-H., M. T., A. V., G. N., O. K.]; Department of Chemistry, University of Sienna, Sienna, Italy [M. T., A. V.]; and Department of Surgery A, Tel-Aviv Medical Center, 6 Weizmann Street, Tel-Aviv 64239, Israel [O. K.]

The mechanism of action of the antineoplastic drug lonidamine (LND) on MCF-7 human breast cancer cells was studied with the use of ³¹P and ¹³C nuclear magnetic resonance (NMR) spectroscopy. The cells were embedded in alginate microcapsules, perfused with growth media and LND at physiological conditions in the NMR tube, and continuously monitored in vivo for the effects of LND. ³¹P NMR demonstrated intracellular acidification after LND perfusion concomitant with ATP depletion and changes in phospholipid metabolites. ¹³C NMR showed marked LND-induced accumulation of lactate, and spectra of the perfusate disclosed that LND inhibited lactate transport. Kinetic ¹³C NMR also furnished information on LND effects on glucose metabolism; LND decreased initial glucose uptake and lactate formation, although the final intracellular glucose levels were higher compared with those in controls. Combined administration of LND and the metabolic inhibitor 2-deoxy-glucose yielded additive but not synergistic cytotoxicity and enabled assessment of hexokinase activity. Overall, the results indicate that the major metabolic changes induced by LND are inhibition of lactate transport and its accumulation, which lead to intracellular acidification.

¹ To whom requests for reprints should be addressed.

Received 1/18/95. Accepted 5/ 3/95.

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