Targeting Lactate Efflux Inhibition for the Development of Potent Antiproliferative Agents

Abstract

In cancer cells, much of the pyruvate from glycolysis is directed away from the mitochondria to form lactate. Monocarboxylate transporters (MCT) mediate the fluxes of lactate and represent an attractive target to inhibit lactate shuttle that maintain tumor growth. In this study, we screened 906 ethanolic plant extracts for their ability to inhibit lactate efflux using Neuroblastoma (N2A) cell line. These extracts were tested at 4 different concentrations (1.0‐0.05 mg/ml) and the obtained results indicate that the plant extracts of Fructus Chebulae (Chinese herb used for cough) and Bupleurum Chinense (an East Asian herb used to treat infections) were very effective inhibitors of lactate efflux at the lowest concentration tested (0.05 mg/ml). Dose‐response curves for Fructus Chebulae and Bupleurum Chinense were established and the IC50 for these 2 plants extracts were 0.003mg/ml and 0.022 mg/ml, respectively. The plant extracts inhibition was more effective than the well‐known MCT inhibitor phloretin which caused inhibition to lactate production with IC50 at 0.048 mg/ml. The data obtained showed that Fructus Chebulae had an inhibitory growth of N2A with EC50 of 0.0038 mg/ml and for Bupleurum Chinense with EC50 of 0.022 mg/ml. Moreover, the effect of these 2 plants on primary rat astrocytes viability was examined and the obtained data indicate that Fructus Chebulae was safer than Bupleurum Chinense (EC50 were 0.018 and 0.021 mg/ml, respectively). In conclusion, the results indicate that the extract of Fructus Chebulae and Bupleurum Chinense were highly selective to inhibit lactate efflux and thus may also inhibit cancer cell proliferation. (Supported by NIH grants from NIMHD G12 MD007582 and P20 MD006738)