Targeting the multidrug resistance-1 transporter in AML: Molecular regulation and therapeutic strategies

Daruka Mahadevan, Alan F. List

Research output: Contribution to journalReview articlepeer-review

132 Scopus citations

Abstract

The multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance-related proteins (MRPs) are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenoblotics across cell membrane barriers. Three-dimensional modeling of human MDR1/P-gp indicates that these glycoproteins function as efficient, ATP-dependent gate-keepers, which scan the plasma membrane and its inner leaflet to flip lipophilic substrates to the outer membrane leaflet. Delineation of the adverse prognostic power of MDR1 in adult acute myeloid leukemia (AML) raised hopes that pharmacologic blockade of P-gp would improve the outcome of conventional cytotoxic therapy, perhaps more so than in any other human malignancy. Phase 3 clinical trials Investigating first- and second-generation P-gp antagonists have yielded conflicting results, emphasizing the Importance of applying preclinical principals to realistically appraise expectations for clinical benefit. Structure-based design strategies and the delineation of transcriptional regulators of survival gene cassettes promise to yield novel, more-effective strategies to overcome drug resistance. Lessons learned from Investigations of these and other mechanisms of cellular defense hold promise for a renaissance in the development of targeted therapeutics in acute leukemia.

Original languageEnglish (US)
Pages (from-to)1940-1951
Number of pages12
JournalBlood
Volume104
Issue number7
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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