Lonidamine (LND) is a relatively new anti-
cancer drug, and several clinical trials have indicated that it may be effective in combinations with other therapeutic modalities. LND is classified within the metabolic inhibitor agents. Multidrug resistance (MDR) phenomenon is often associated with increased energy requirements, and enhanced glycolysis rate. These studies were performed to delineate the mechanism of action of LND on MDR human
breast cancer cells, and to investigate whether LND as a single agent, or in combination with another anti-metabolism
drug,
2-deoxyglucose (2-DG), may be useful against MDR
tumors. The effects of LND on intact perfused
drug-sensitive (WT) and 33-fold resistant to
Adriamycin (Adr) MCF-7 cells, embedded in
alginate micro capsules, were continuously monitored by 31P and 13C nuclear magnetic resonance (NMR) spectroscopy. 31P NMR studies showed that LND induced intracellular acidification and depletion of NTP in both WT and Adr cells. However, pH and NTP levels decreased less in the Adr cells than in the WT cells (p < 0.05 for both parameters). 13C NMR demonstrated that LND inhibited
lactate transport, and
lactate signals were elevated in both cell lines. However, the intracellular
lactate levels increased to a greater extent in the WT than in the Adr cells (p < 0.05). There were major differences in the effects of LND on metabolism between sensitive and resistant cells. While LND enhanced
glucose uptake in the WT cells, and its administration was followed by continuous increase of
lactate signal, both processes were not affected by LND in the Adr cells. 2-DG is a
glucose analogue that inhibits both cellular uptake and utilization of
glucose, leading to cell
starvation. Combined treatment with LND and 2-DG yielded at best additive, but not synergistic, cellular toxicity, and the metabolic effects of LND were attenuated by 2-DG. These results showed that the principal mechanism of action of LND is inhibition of
lactate transport leading to intracellular
lactate accumulation and acidification in both WT and Adr cells. The Adr cells were only 2-fold resistant to LND (compared to the WT cells), and since cellular uptake of
alkaloid chemotherapy is improved in acidic environment, LND may have a role in the treatment protocols of MDR
tumors, especially when given as the initial means for induction of intracellular acidification.