Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells.
Imatinib is actively transported by organic cation transporter-1 (OCT-1) influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Herein we report that, in diagnostic chronic myeloid leukemia mononuclear cells andBCR-ABL1+cell lines, peroxisome proliferator-activated receptor γ agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor γ antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to BCR-ABL kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor γ-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor γ transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84;P<0.0001), suggesting that peroxisome proliferator-activated receptor γ activation has a negative impact on the intracellular uptake of imatinib and consequent BCR-ABL kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor γ activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor γ agonist pioglitazone was reported to act synergistically with imatinib, targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor γ ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor γ activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor γ transcriptional activity.
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.|School of Medicine, University of Adelaide, Australia.
Jueqiong
J
Wang
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.|School of Medicine, University of Adelaide, Australia.
Liu
L
Lu
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.|School of Medicine, University of Adelaide, Australia.
Chung H
CH
Kok
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
Verity A
VA
Saunders
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
Jarrad M
JM
Goyne
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.
Phuong
P
Dang
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.|School of Medicine, University of Adelaide, Australia.
Tamara M
TM
Leclercq
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.|School of Medicine, University of Adelaide, Australia.|Department of Haematology, SA Pathology, Adelaide, Australia.|Australasian Leukaemia and Lymphoma Group, Melbourne, Australia.
Timothy P
TP
Hughes
Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia deborah.white@sahmri.com.|School of Medicine, University of Adelaide, Australia.|Australasian Leukaemia and Lymphoma Group, Melbourne, Australia.
Deborah L
DL
White
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D027702:Organic Cation Transporter 1; D047495:PPAR gamma; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl