Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism
In: Journal of the National Cancer Institute, Jg. 92 (2000), Heft 11, S. 898-902
Online
academicJournal
- print, 33 ref
Zugriff:
Background: P-glycoprotein (P-gp) pumps a wide range of cytotoxic drugs out of cells. Inhibiting maturation of P-gp would be a novel method for circumventing P-gp-mediated multidrug resistance, which complicates cancer chemotherapy and treatment of patients infected with human immunodeficiency virus. We examined the effect of disulfiram (Antabuse) on the maturation and activity of P-gp. Methods: Embryonic kidney cells were transfected with a complementary DNA for the P-pg gene, and the effects of disulfiram on the sensitivity of the transfected cells to cytotoxic agents were determined. Enzyme assays were used to determine the effects of disulfiram on the verapamil-stimulated adenosine triphosphatase (ATPase) activity of P-gp. Disulfiram modifies cysteine residues, and mutant forms of P-gp that lack individual cysteines were used to determine whether particular cysteine residues mediate disulfiram's effects on P-gp activity. Maturation of recombinant P-gp was followed on immunoblots. Results: Disulfiram increased the sensitivity of P-gp-transfected cells to vinblastine and colchicine and inhibited P-gp's verapamil-stimulated ATPase activity. Half-maximal inhibition of ATPase activity occurred at 13.5 μM disulfiram. Disulfiram (at 100 μM) inhibited a P-gp mutant by 43% (95% confidence interval [CI] = 37%-48%) when cysteine was present at position 431 only and by 72% (95% CI = 66%-77%) when cysteine was present at position 1074 only. Treatment of P-gp-transfected cells with 50 nM disulfiram blocked maturation of recombinant P-gp. Conclusions: Disulfiram can potentially reduce P-gp-mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation. These results suggest that disulfiram has the potential to increase the efficacy of drug therapies for cancer and acquired immunodeficiency syndrome.
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Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism
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Autor/in / Beteiligte Person: | LOO, Tip W ; CLARKE, David M |
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Zeitschrift: | Journal of the National Cancer Institute, Jg. 92 (2000), Heft 11, S. 898-902 |
Veröffentlichung: | Cary, NC: Oxford University Press, 2000 |
Medientyp: | academicJournal |
Umfang: | print, 33 ref |
ISSN: | 0027-8874 (print) |
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