The poor response to imatinib observed in CML patients with low OCT-1 activity is not attributable to lower uptake of imatinib into their CD34+ cells

Engler, Jane R.; Frede, Amity; Saunders, Verity A.; Zannettino, Andrew C.W.; White, Deborah L.; Hughes, Timothy P.

doi:10.1182/blood-2010-01-267013

Cited by 20 publications

(12 citation statements)

References 22 publications

(27 reference statements)

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“…In addition, OA in CD34 + is not predictable for the achievement of major molecular response (MMR). 35 Given that diagnostic peripheral blood MNC samples is the cell population in which the predictive value of OA was established, this cell population was investigated in the current study. While the proposed PPARγ ligand-TKI combination therapy can effectively target leukemic stem cells, the contradictory effect of PPARγ on intracellular imatinib uptake and retention observed in circulating MNC, suggests that it may not be an ideal option for de novo CP-CML patients on imatinib, as a rapid initial decline in BCR-ABL1 transcripts is critical for improved event-free survival.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Recently, Engler et al suggested that the poor response to imatinib is not associated with the uptake of imatinib into primitive CD34ϩCML cells. 23) According to this study, the reason for no relationship between the intracellular concentration and response may not be due to no separation between mature leukocytes and leukemia initiating cells. Therefore, in patients without CCR, intrinsic property of leukemic cells such as mutations of BCR-ABL, or alternative survival pathways could be responsible for imatinib insensitivity, [24][25][26][27] because the intracellular and plasma concentration of imatinib are comparable between the patients with and without CCR.…”

Section: Discussionmentioning

confidence: 99%

Association of SLCO1B3 Polymorphism with Intracellular Accumulation of Imatinib in Leukocytes in Patients with Chronic Myeloid Leukemia

Nambu

Hamada

Nakashima

et al. 2011

Biological & Pharmaceutical Bulletin

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Intracellular concentration of imatinib in leukemic cells is thought to affect the clinical efficacy of this drug in patients with chronic myeloid leukemia (CML); however, there is no report that directly indicates the relationship between intracellular concentration and clinical outcome and/or, plasma concentration. In addition, the impacts of genetic variations of drug transporters, which mediate leukocyte concentration of imatinib, are unknown. In the present study, we investigated the correlation between intracellular imatinib concentrations in leukocytes, plasma imatinib levels, and genotypes of drug transporters, including ATP binding cassette B1 (ABCB), ABCG2, solute carrier 22A1 (SLC22A1), solute carrier organic anion transporter family members 1B1 (SLCO1B1) and SLCO1B3. The imatinib levels in leukocytes were determined using HPLC in 15 patients with chronic phase CML. No significant correlation between intracellular and plasma concentrations of imatinib was observed. The intracellular concentration was comparable in both patients with or without complete cytogenetic response. The intracellular imatinib concentration was significantly higher in patients with SLCO1B3 334TT than in those with 334TG/GG ( p‫؍‬ ‫.)8810.0؍‬ Plasma concentrations were similar in both SLCO1B3 genotypes (p‫؍‬ ‫,)068.0؍‬ thereby resulting in the intracellular to plasma concentration ratio being higher in patients with SLCO1B3 334TT than those with 334 TG/GG ( p‫؍‬ ‫.)2050.0؍‬ These results suggested that the SLCO1B3 334TϾ ϾG polymorphism could have a significant impact on the intracellular concentration of imatinib in leukocytes as a promising biomarker for personalized treatment of CML patients.

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“…When prazosin, an OCT1 inhibitor, was added to these cells, the concentration needed to inhibit molecular drug targets was significantly increased. Furthermore, it was also shown that only the activity of OCT1 in mature CML blasts is associated with therapeutic outcome and not the OCT1 activity in immature CD34 þ cells (64).…”

Section: Drug Transporters and Imatinib Pharmacodynamicsmentioning

confidence: 99%

Drug Transporters and Imatinib Treatment: Implications for Clinical Practice

Eechoute

Sparreboom

Burger

et al. 2011

Clinical Cancer Research

139

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Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as "acquired pharmacokinetic drug resistance." This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations.

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The poor response to imatinib observed in CML patients with low OCT-1 activity is not attributable to lower uptake of imatinib into their CD34+ cells

Cited by 20 publications

References 22 publications

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

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

Association of SLCO1B3 Polymorphism with Intracellular Accumulation of Imatinib in Leukocytes in Patients with Chronic Myeloid Leukemia

Drug Transporters and Imatinib Treatment: Implications for Clinical Practice

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