Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML).
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.
Tang
Ruoping
R
INSERM, U872 Equipe 18 Paris, F-75006 France. ruoping.tang@htd.aphp.fr
Faussat
Anne-Marie
AM
Perrot
Jean-Yves
JY
Marjanovic
Zora
Z
Cohen
Simy
S
Storme
Thomas
T
Morjani
Hamid
H
Legrand
Ollivier
O
Marie
Jean-Pierre
JP
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; C095179:zosuquidar trihydrochloride