Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications.
OBJECTIVE
The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed.


METHODS
The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors.


RESULTS
Unlike imatinib, there was no significant difference in the dasatinib IUR at 37 degrees C and 4 degrees C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50(dasatinib) values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50(dasatinib) (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC(50)(dasatinib).


CONCLUSIONS
Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.
Hiwase
Devendra K
DK
Division of Haematology, Institute of Medical and Veterinary Science, University of Adelaide, Adelaide, South Australia, Australia.
Saunders
Verity
V
Hewett
Duncan
D
Frede
Amity
A
Zrim
Stephanie
S
Dang
Phuong
P
Eadie
Laura
L
To
L Bik
LB
Melo
Junia
J
Kumar
Sharad
S
Hughes
Timothy P
TP
White
Deborah L
DL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides; D001692:Biological Transport / Q000187:drug effects; D000069439:Dasatinib; D004353:Drug Evaluation, Preclinical; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013696:Temperature; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib