title: Triggering noncycling hematopoietic progenitors and leukemic blasts to proliferate increases anthracycline retention and toxicity by downregulating multidrug resistance.
abstract: Expression of the multidrug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34(+) progenitors showed rhodamine efflux in 20% to 30% of the cells, which could be blocked by verapamil. These cells appeared noncycling, in contrast to the proliferating rhodamine bright (RhoB) cells. We postulated that MDR expression can be downregulated by proliferation induction. Triggering rhodamine dull (RhoD) CD34(+) cells to proliferate indeed resulted in a higher rhodamine retention and significantly decreased efflux modulation by verapamil (P =.04). Also in acute myeloid leukemia (AML), the proliferation rate (percentage S/G(2)+M and Iododeoxyuridine labelings index) was significantly less in the RhoD blasts (P </=. 008) and proliferation induction of RhoD blasts resulted in increased rhodamine retention. Anthracycline cytotoxicity was less for RhoD than RhoB cells in both normal progenitors and leukemic blasts. Proliferation induction of the RhoD cells resulted in increased anthracycline sensitivity. We conclude that noncycling progenitors, both normal and leukemic, have a relatively high MDR expression. Triggering these cells into proliferation downregulates MDR expression. These findings can be exploited to overcome MDR in the treatment of AML patients.
authors.affiliation: Division of Hematology, University Hospital Nijmegen, Nijmegen, The Netherlands. M.Smeets@hemat.azn.nl
authors.forename: M E
authors.initials: ME
authors.lastname: Smeets
authors.forename: R A
authors.initials: RA
authors.lastname: Raymakers
authors.forename: G
authors.initials: G
authors.lastname: Vierwinden
authors.forename: A H
authors.initials: AH
authors.lastname: Pennings
authors.forename: H
authors.initials: H
authors.lastname: Wessels
authors.forename: T
authors.initials: T
authors.lastname: de Witte
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D018952:Antigens, CD34; D001752:Blast Crisis / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003630:Daunorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D015255:Idarubicin / Q000633:toxicity; D007065:Idoxuridine; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D018952:Antigens, CD34; D014700:Verapamil; D007065:Idoxuridine; D015255:Idarubicin; D003630:Daunorubicin