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|Title:||Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells|
|Other Titles:||Increased peroxisome proliferator-activated receptor gamma activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells|
|Citation:||Haematologica, 2017; 102(5):843-853|
|Publisher:||Ferrata Storti Foundation|
|Jueqiong Wang, Liu Lu, Chung H. Kok, Verity A. Saunders, Jarrad M. Goyne, Phuong Dang, Tamara M. Leclercq, Timothy P. Hughes and Deborah L. White|
|Abstract:||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 and BCR-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.|
|Keywords:||Leukocytes, Mononuclear; Cells, Cultured; Cell Line, Tumor; HL-60 Cells; K562 Cells; Humans; Leukemia, Myeloid, Chronic-Phase; Organic Cation Transporter 1; Fusion Proteins, bcr-abl; PPAR gamma; Antineoplastic Agents; Gene Expression Regulation, Leukemic; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imatinib Mesylate|
|Rights:||© 2017 Ferrata Storti Foundation|
|Appears in Collections:||Medicine publications|
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