Multidrug-resistant MCF-7 Human Breast Cancer Cells: Action of Gossypol and Rhodamine 123 on Wild Type and Updated Version

The action of gossypol, a polyphenolic bisnaphthalene aldehyde, on a number of drug-sensitive and multidrug-resistant cell lines, in particular MCF-7 WT and MCF-7 ADR cells, was studied and compared to the effects of rhodamine 123. " P nuclear magnetic resonance spectra of cells exposed to low concentrations of gossypol exhibited decreased levels of ATP, markedly increased levels of pyridine nucleotides, and decreased levels of glycerylphosphocholine. The latter effect may be related to the membrane viscosity-increasing effect of gossypol, whereas changes in the levels of pyridine nucleotides are probably due to an interference with NADand NADP-dependent enzymes. The effect of gossypol represents a rare example of selective and differentiated changes observed in "P nuclear magnetic resonance spectra of cells following exposure to a drug; the effect was markedly different from that of rhodamine 123, which caused ATP depletion but no changes in the levels of glycerylphospho choline or pyridine nucleotides. Also, the effects of gossypol and rhoda mine 123 on glucose metabolism in the MCF-7 WT cells were different. Thus although both drugs caused a marked elevation of glucose uptake, an increase in lactate production exceeding that of glucose consumption, indicating an inhibition of oxidative phosphorylation, was observed only in the case of rhodamine 123. Significantly, multidrug-resistant cells exhibited strong cross-resistance to rhodamine but practically no resist ance to gossypol, which emphasizes the attractiveness of the latter as a potential anticancer drug. The resistance to rhodamine 123 and sensitivity to gossypol was also observed with cells transfected with the MDRI gene, showing that the difference in toxicity is mainly due to the different response to the P-1"II drug efflux pump.