A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia

Leukemia
D W HedleyV Ling

Abstract

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin and P-gp antigen expression (Xie et al, Leukemia 1995; 9:1882-1887). This discordance suggests that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin...Continue Reading

Citations

Aug 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Thiha AungGerald G Wulf
Jul 1, 2009·Journal of Pediatric Hematology/oncology·Jacek BrozekJacek M Witkowski
Sep 7, 2000·Journal of Clinical Pharmacology·J P DutcherP H Wiernik
Feb 19, 2002·Oncogene·Simon W-L Chan, Elizabeth H Blackburn
Feb 25, 2014·Multiple Sclerosis : Clinical and Laboratory Research·Riley Bove, Tanuja Chitnis

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