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MN Benchekroun, E Schneider, AR Safa, AJ Townsend and BK Sinha
Biochemical and Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
We recently reported that multidrug-resistant, P-170 glycoprotein- positive, Adriamycin-selected, human breast tumor (MCF7/ADRR) cells were resistant to the benzoquinonoid ansamycin antibiotics geldanamycin (GL) and herbimycin A (HA) and that significantly fewer hydroxyl radicals were formed in resistant cells. We have carried out additional studies to define the mechanisms of cytotoxicity of and resistance to GL and HA, by directly examining the interactions of these drugs with P- 170 glycoprotein using photoaffinity labeling. We found that both GL and HA inhibited binding of azidopine to P-170 glycoprotein in a dose- dependent manner. We have developed a 10-fold GL-resistant cell line (MCF7/GLR) by continuous drug exposure. Our studies indicated no significant differences in free radical formation between wild-type MCF7 cells and MCF7/GLR cells. Uptake and efflux studies indicated a small decrease in the GL accumulation but no difference in the efflux of GL in these cells. Verapamil had no effect on cellular accumulation of GL in wild-type MCF7 cells or MCF7/GLR cells. Verapamil significantly increased the accumulation of GL in MCF7/ADRR cells and enhanced GL cytotoxicity 12-fold, suggesting that GL interacted with the P-170 glycoprotein. Using reverse transcription-polymerase chain reaction, we found no expression of the mdr1 gene; however, expression of the multidrug resistance-associated protein was about 2-fold higher in MCF7/GLR cells. Taken together, these studies indicate that the mechanisms of GL resistance are multifactorial. Although decreased free radical formation may not play a significant role in low levels of GL resistance, e.g., in MCF7/GLR cells, both overexpression of mdr1 and decreased free radical formation contribute to GL resistance in highly resistant cells such as MCF7/ADRR cells.
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