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Energy Metabolism of Human LoVo Colon Carcinoma Cells: Correlation to Drug Resistance and Influence of Lonidamine¹

Laboratory of Cell Metabolism and Pharmacokinetics, Center for Experimental Research, Regina Elena Cancer Institute, Rome, Italy [M. F., T. B., M. D. P., A. F.]; Department of Experimental Medicine, University of L’Aquila, 67100 L’Aquila, Italy [A. G., A. F.]; and Laboratories of Biophysics [A. G.] and Medical Physics [F. P. G., O. R.], Center for Experimental Research, Regina Elena Cancer Institute, 00158 Rome, Italy

The relationship between modification of energy metabolism and extent of drug resistance was investigated in two sublines (LoVoDX and LoVoDX₁₀) from human LoVo colon carcinoma cells that exhibit different degrees of resistance to doxorubicin. Results indicated that the extent of alteration in energy metabolism strictly correlated with degree of resistance. In LoVoDX cells, only ¹⁴CO₂ production was enhanced, whereas in the more resistant LoVoDX₁₀ cells, both ¹⁴CO₂ and aerobic lactate production were stimulated. The basal and glucose-supported efflux rate and the amount of drug extruded by LoVoDX₁₀ cells were significantly higher than in the resistant LoVoDX cells. Because the expression of surface P-170 glycoprotein was similar in both cell lines, this phenomenon was attributed to increased efflux pump activity resulting from greater ATP availability. Inhibition of ¹⁴CO₂ production, aerobic glycolysis, and clonogenic activity by lonidamine (LND) increased with enhancement of the energy metabolism. Moreover, LND, by affecting energy-yielding processes, reduced intracellular ATP content, lowered the energy supply to the ATP-driven efflux pump, and inhibited, almost completely, doxorubicin extrusion by resistant LoVo cells. These findings strongly suggest that LND, currently used in tumor therapy, reduces drug resistance by restoring the capacity to accumulate and retain drug of cells with the MDR phenotype that overexpress P-170.

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				A. Floridi Reply Clin. Cancer Res., October 1, 2000; 6(10): 4166- - 4167. [Abstract] [Full Text]