Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype

Robert J. Arceci, Kimberly Stieglitz, Barbara E. Bierer

Research output: Contribution to journalArticle

Abstract

The multidrug-resistant (MDR) phenotype is characterized in vitro by the resistance displayed by cell lines to a broad spectrum of natural product cytotoxic agents. This high level of cross-resistance is due to the increased expression of a membrane glycoprotein termed P-glycoprotein. Encoded in humans by the mdr1 gene, P-glycoprotein functions as an energy-dependent efflux pump of these cytotoxic agents. In this report, we demonstrate that the newly characterized immunosuppressant FK506 and its structural analogue, rapamycin, are capable of functioning as MDR reversal agents. FK506 and rapamycin increase both intracellular, cytotoxic drug (daunomycin) accumulation, and the cytotoxicity of chemotherapeutic agents in multidrug-resistant cells. The increase in cytotoxic drug accumulation is observed at concentrations of FK506 and rapamycin 1,000-fold greater than the concentrations required for FK506 and rapamycin to inhibit T-lymphocyte activation and similar to those shown to be effective for other MDR reversal agents such as cyclosporine A (CsA) and verapamil. The effect of FK506 or rapamycin on both intracellular accumulation and cytotoxicity of daunomycin is additive. This is supported by the ability of FK506 and rapamycin to directly compete the binding of the photoaffinity analogue 125I-iodoaryl azidoprazosin to the P-glycoprotein. The data demonstrate that FK506 and rapamycin represent a new class of structurally distinct molecules that can function as MDR reversal agents and suggest a previously unidentified, potential clinical role for these compounds.

Original languageEnglish (US)
Pages (from-to)1528-1536
Number of pages9
JournalBlood
Volume80
Issue number6
StatePublished - Sep 15 1992
Externally publishedYes

Fingerprint

Multiple Drug Resistance
Tacrolimus
Sirolimus
Immunosuppressive Agents
Phenotype
P-Glycoprotein
Daunorubicin
Cytotoxins
Cytotoxicity
T-cells
Membrane Glycoproteins
Lymphocyte Activation
Verapamil
Biological Products
Pharmaceutical Preparations
Cyclosporine
Genes
Chemical activation
Cells
Pumps

ASJC Scopus subject areas

  • Hematology

Cite this

Arceci, R. J., Stieglitz, K., & Bierer, B. E. (1992). Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. Blood, 80(6), 1528-1536.

Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. / Arceci, Robert J.; Stieglitz, Kimberly; Bierer, Barbara E.

In: Blood, Vol. 80, No. 6, 15.09.1992, p. 1528-1536.

Research output: Contribution to journalArticle

Arceci, RJ, Stieglitz, K & Bierer, BE 1992, 'Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype', Blood, vol. 80, no. 6, pp. 1528-1536.
Arceci, Robert J. ; Stieglitz, Kimberly ; Bierer, Barbara E. / Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. In: Blood. 1992 ; Vol. 80, No. 6. pp. 1528-1536.
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