hOCT 1 and resistance to imatinib

Crossman, Lucy C.; Druker, Brian J.; Deininger, Michael W.

doi:10.1182/blood-2005-02-0694

Cited by 183 publications

(148 citation statements)

References 6 publications

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“…However, other mechanisms have also been implicated including the duplication and amplification of the BCR-ABL (Weisberg and Griffin, 2000;le Coutre et al, 2000). Imatinib export via the p-glycoprotein efflux pump (Mahon et al, 2000), reduced expression of the organic cation transporter OCT1 (Crossman et al, 2005;Wang et al, 2008), binding of imatinib to the plasma by a1-acid glycoprotein (Gambacorti-Passerini et al, 2003a) and the activation of alternative signaling cascades leading to BCR-ABL-independent growth (Donato et al, 2003;Ptasznik et al, 2004). With regard to STAP-2 expression, one gene expression database on CML patient samples reported that STAP-2 was expressed by CD34 þ cells (D Bruennert, 2009).…”

Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-2. In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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“…Resistance to imatinib caused by BCR-ABL gene amplification or increased levels of mRNA can be overcome by increasing the imatinib dose [6][7][8] . More recently, it has been suggested that variations in imatinib trough plasma concentrations (C mins ) could affect cytogenetic and molecular responses in CML.…”

Section: Introductionmentioning

confidence: 99%

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients. Methods: Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (C mins ) with the patients' characteristics and responses were analyzed. Results: The overall mean (±SD, CV%) steady-state C mins for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (±583.53 ng/mL; 44%) and 1550.90 ng/mL (±462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher C mins than the male patients (P=0.048), and molecular responses were not correlated with imatinib C mins , but they were correlated with time elapsed before imatinib therapy. Conclusion:The results suggest that Chinese CML patients have higher imatinib C mins than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.

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“…The putative clinical significance of potential imatinib uptake transporters has extensively been investigated in the last decade as reflected by the numerous (pre-) clinical studies that have been conducted to investigate their role in the pharmacokinetics and/or pharmacodynamics of imatinib (Thomas et al, 2004;Crossman et al, 2005;White et al, 2006White et al, , 2007White et al, , 2010Hu et al, 2008;Wang et al, 2008;White and Hughes, 2012;Nies et al, 2014). SLC22A1, also referred to as organic cation transporter (OCT) 1, has frequently been implicated in the intracellular uptake and disposition of imatinib in CML cells (Thomas et al, 2004;White et al, 2006), although controversy exists with regard to its precise role (Burger et al, 2013;Nies et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Lysosomal Sequestration Determines Intracellular Imatinib Levels

et al. 2015

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The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy-dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH 4 Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression.

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hOCT 1 and resistance to imatinib

Cited by 183 publications

References 6 publications

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients

Lysosomal Sequestration Determines Intracellular Imatinib Levels

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