Evidence of a role for functional heterogeneity in multidrug resistance transporters in clinical trials of P-glycoprotein modulation in acute myeloid leukemia

John F. Marcelletti, Branimir I. Sikic, Larry D. Cripe, Elisabeth Paietta

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: Multidrug resistance (MDR) transporter proteins such as P-glycoprotein (P-gp) efflux a variety of chemotherapeutic drugs from acute myeloid leukemia (AML) blasts leading to clinical drug resistance. Methods: This study examined heterogeneity of MDR functional efflux by AML blasts using two flow cytometry bioassays. Bone marrow specimens (N = 50) from elderly patients with newly diagnosed AML were analyzed for CD34+ blasts with MDR efflux function. Efflux was measured with a fluorescent dye (DiOC 2 ) as a surrogate for oncology drugs that are substrates for MDR efflux. P-gp-mediated efflux was differentiated from non-P-gp MDR activities using zosuquidar, a highly selective P-gp modulator. The bioassays included a zosuquidar-dependent DiOC 2 accumulation bioassay that measured only P-gp. The second method, termed the efflux bioassay, could detect P-gp and other non-P-gp efflux depending on bioassay culture conditions. Results: Sixty-two percent of the specimens were considered positive for blasts with P-gp function, and 26% of such P-gp-positive specimens also exhibited zosuquidar-resistant (i.e., non-P-gp) MDR efflux activity; 37% of P-gp-negative AML blast specimens displayed zosuquidar-resistant MDR function in the efflux bioassay. Conclusions: These results confirm the heterogeneous nature of MDR efflux pumps in AML blasts, and provide support for the hypothesis that non-P-gp MDR contributed to negative results with zosuquidar in AML trials like ECOG-ACRIN E3999.

Original languageEnglish (US)
Pages (from-to)57-66
Number of pages10
JournalCytometry Part B - Clinical Cytometry
Volume96
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • acute myeloid leukemia
  • drug transporters
  • multidrug resistance

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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