title: Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML).
abstract: BACKGROUND
  Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts.
  
  
  METHODS
  The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test.
  
  
  RESULTS
  Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp.
  
  
  CONCLUSIONS
  These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients.
authors.affiliation: INSERM, U872 Equipe 18 Paris, F-75006 France. ruoping.tang@htd.aphp.fr
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Faussat
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Perrot
authors.forename: Zora
authors.initials: Z
authors.lastname: Marjanovic
authors.forename: Simy
authors.initials: S
authors.lastname: Cohen
authors.forename: Thomas
authors.initials: T
authors.lastname: Storme
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Ollivier
authors.initials: O
authors.lastname: Legrand
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marie
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D003986:Dibenzocycloheptenes / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; C095179:zosuquidar trihydrochloride