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Reply to ‘Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels’ by Widmer et al.

Leukemia volume 21, pages 1562–1563 (2007)Cite this article

The letter of Widmer et al. describes that the silencing of MDR1 expression by specific small interfering RNA (siRNA) resulted in the increased intracellular levels of imatinib in doxorubicin-selected K562 cells.1 Their finding is consistent with the previously reported concept that imatinib is a substrate for P-glycoprotein (P-gp),2, 3 and rules out other possibilities that could lead to restoration of imatinib sensitivity. However, we found that specific elimination of P-gp expression in the hematopoietic system did not improve responses to imatinib in a chronic myelogenous leukemia (CML) animal model; leukemia initiating cells were not sensitized to imatinib by loss of P-gp, indicating the negligible role of P-gp in resistance to imatinib in vivo.4 In line with our findings, a recent study in patients with gastrointestinal stromal tumors (GIST) showed that the pharmacokinetic parameters of imatinib in vivo were not related to any of the defective variant genotypes of ABCG2 or MDR1 alleles examined, indicating the activity of these two ATP-binding cassette (ABC) transporters have limited clinical significance on the pharmacokinetics of imatinib.5 Consistently, in another study of 21 GIST patients, no significant correlation between ABC transporters expression and the risk assessment was observed; none of the six patients treated with imatinib were resistant, although all were positive for expression of at least one ABC transporter.6 As discussed previously, the contribution of P-gp expression to clinical imatinib resistance in CML also appears to be limited.7

We proposed that this paradox could be possibly explained by the inhibitory effects of imatinib on the efflux function of P-gp and other ABC transporters. We (data not shown) and others3, 8, 9 found that incubation with high concentrations of imatinib led to potent functional inhibition of P-gp as well as ABCG2. Given the similar molecular structures between imatinib and ATP, it is possible that the abrogation of transporter function may result from competitive binding of imatinib to ATP-binding sites on the nucleotide-binding domain of ABC transporters, which could make the ABC transporter-expressing cells display an ABC transporter null phenotype. Moreover, Nakanishi et al.10 recently described that ABCG2-overepressing K562 cells only displayed modest resistance to the low concentration of imatinib. It has been also showed that imatinib could decrease the expression of ABCG2 post-transcriptionally in BCR-ABL positive cells, and this downregulation of ABCG2 expression may occur via inhibition of PI3K/Akt pathway. So imatinib-induced reduction of ABCG2 protein expression could also attenuate the resistance to imatinib.10 Taken together, it seems that imatinib can abolish the protective effects of ABC transporters by both ATP depletion and downregulation of transporter expression, which make the interaction of imatinib with ABC transporters more complicated than it appears to be. Therefore, more studies are required to dissect carefully this complexity in different contexts.

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References

  1. Widmer N, Rumpold H, Untergasser G, Fayet A, Buclin T, Decosterd LA . Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia (in press).

  2. Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF . Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 2003; 304: 1085–1092.

    Article  CAS  PubMed  Google Scholar 

  3. Hamada A, Miyano H, Watanabe H, Saito H . Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther 2003; 307: 824–828.

    Article  CAS  PubMed  Google Scholar 

  4. Zong Y, Zhou S, Sorrentino BP . Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 2005; 19: 1590–1596.

    Article  CAS  PubMed  Google Scholar 

  5. Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G et al. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther 2006; 80: 192–201.

    Article  CAS  PubMed  Google Scholar 

  6. Theou N, Gil S, Devocelle A, Julie C, Lavergne-Slove A, Beauchet A et al. Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. Clin Cancer Res 2005; 11: 7593–7598.

    Article  CAS  PubMed  Google Scholar 

  7. Zong Y, Zhou S, Sorrentino BP . Reply to Rumpold et al. Leukemia 2006; 20: 144–145.

    Article  CAS  PubMed  Google Scholar 

  8. Houghton PJ, Germain GS, Harwood FC, Schuetz JD, Stewart CF, Buchdunger E et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 2004; 64: 2333–2337.

    Article  CAS  PubMed  Google Scholar 

  9. Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC . Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood 2006; 108: 1370–1373.

    Article  CAS  Google Scholar 

  10. Nakanishi T, Shiozawa K, Hassel BA, Ross DD . Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression. Blood 2006; 108: 678–684.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Experimental Hematology, Department of Hematology–Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    Y Zong, S Zhou & B P Sorrentino

  2. The Interdisciplinary Program, College of Graduate Health Sciences, the University of Tennessee Health Science Center, Memphis, TN, USA

    Y Zong & B P Sorrentino

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  1. Y Zong
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Correspondence to B P Sorrentino.

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Zong, Y., Zhou, S. & Sorrentino, B. Reply to ‘Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels’ by Widmer et al.. Leukemia 21, 1562–1563 (2007). https://doi.org/10.1038/sj.leu.2404672

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