Increased peroxisome proliferator-activated receptor γ activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells

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.

Efficacy and safety of pioglitazone in a phase 1/2 imatinib discontinuation trial (EDI‐PIO) in chronic myeloid leukemia with deep molecular response

“…6 The authors suggest that the effect of PPAR-gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, particularly in patients with high PPAR-gamma activity. 5 In our study, the TFR rate at 12 months was consistent with other imatinib discontinuation trials, such as the Korean trial and A-STIM and slightly superior to TWISTER, probably due to differences in the imatinib reintroduction criteria. 1 Treatment-free remission was estimated as 64% at 12 and 24 months, and 61% at 36 months in the A-STIM trial.…”

“…In our study, (OCT-1) activity. 5 The authors suggest that the effect of PPAR-gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, particularly in patients with high PPAR-gamma activity. 6 Note, OCT-1 activity is a predictor of long term outcome in CML patients treated with imatinib.…”

“…However, the benefit of this combination is complex and needs further evaluation. Wang et al have demonstrated that in diagnostic CML mononuclear cells and BCR‐ABL1 + cell lines, PPAR‐gamma significantly decreases organic cation transporter‐1 (OCT‐1) activity 5 . The authors suggest that the effect of PPAR‐gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, particularly in patients with high PPAR‐gamma activity 6 .…”

“…Note, OCT‐1 activity is a predictor of long term outcome in CML patients treated with imatinib 6 . The authors suggest that the effect of PPAR‐gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, particularly in patients with high PPAR‐gamma activity 5 …”

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review

“…Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a transcription factor that may interfere with the action of the protein OCT-1, which, as previously explained, is related to the transport of imatinib into BCR-ABL1 + cells, among other functions[ 187 ]. The ligands of PPAR-γ, such as pioglitazone, are drugs currently used to treat diabetes that have demonstrated utility in the therapy of CML[ 188 ].…”