Action of gossypol and rhodamine 123 on wild type and multidrug-resistant MCF-7 human breast cancer cells: 31P nuclear magnetic resonance and toxicity studies.
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.
Biophysical Pharmacology Section, National Cancer Institute, NIH, Bethesda, Maryland 20892.
J W
JW
Jaroszewski
O
O
Kaplan
J S
JS
Cohen
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance; D005260:Female; D005947:Glucose / Q000378:metabolism; D006072:Gossypol / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007773:Lactates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D010758:Phosphorus; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D007773:Lactates; D012235:Rhodamines; D020112:Rhodamine 123; D010758:Phosphorus; D005947:Glucose; D006072:Gossypol