Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein.
We evaluated the multidrug resistance (MDR)-modulating effects of progesterone (PRG) and an orally active, structurally related compound, megestrol acetate (MA), in several MDR human cell lines. At 100 microM, both steroids inhibited the binding of a Vinca alkaloid photoaffinity analog to P-glycoprotein (P-gp) in MDR human neuroblastic SH-SY5Y/VCR cells [which show greater than 1500-fold resistance to vincristine (VCR) in the tetrazolium dye (MTT) assay]. However, 100 microM MA markedly enhanced the binding of [3H]-azidopine to P-gp in both SH-SY5Y/VCR cells and the MDR human epidermoid KB-GSV2 cell line (which displays 250-fold resistance to VCR in the MTT assay). PRG had little effect on the binding of [3H]-azidopine to P-gp. MA at low doses was more effective than PRG in sensitizing cells to VCR and enhancing their accumulation of [3H]-VCR. The highly resistant SH-SY5Y/VCR subline exhibited significant collateral sensitivity to both steroids. These data suggest that MA may be a clinically useful modulator of MDR.
Department of Medicine, University of Chicago, Ill.
G F
GF
Fleming
J M
JM
Amato
M
M
Agresti
A R
AR
Safa
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000818:Animals; D001386:Azides / Q000378:metabolism; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D004095:Dihydropyridines / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008535:Megestrol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019290:Megestrol Acetate; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology; D014316:Tritium; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology; D014751:Vindesine / Q000031:analogs & derivatives / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D001386:Azides; D004095:Dihydropyridines; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D014316:Tritium; C048695:N-(4-azido-3-iodosalicyl)-N'-beta-aminoethylvindesine; D011374:Progesterone; D014750:Vincristine; C041130:azidopine; D008535:Megestrol; D014751:Vindesine; D019290:Megestrol Acetate