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. 31P 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
NAD- and
NADP-dependent
enzymes. The effect of
gossypol represents a rare example of selective and differentiated changes observed in 31P 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 glycerylphosphocholine or
pyridine nucleotides. Also, the effects of
gossypol and
rhodamine 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 resistance 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 MDR1 gene, showing that the difference in toxicity is mainly due to the different response to the P-170
drug efflux pump.