Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells

Arimany-Nardi, Cristina; Montraveta, Arnau; Lee-Vergés, Eriong; Puente, Xosé S.; Koepsell, Hermann; Campo, Elı́as; Colomer, Dolors; Pastor‐Anglada, Marçal

doi:10.1038/tpj.2014.77

Cited by 17 publications

(14 citation statements)

References 39 publications

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“…Moreover, bendamustine engages cell death through both apoptotic and non-apoptotic pathways, thereby retaining activity even in cells with dysfunctional apoptotic machinery [ 24 ]. Recently, it has been reported that some membrane transporters might also contribute to the cytotoxic effect of bendamustine [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

et al. 2015

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Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases.

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Section: Introductionmentioning

confidence: 99%

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

et al. 2015

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“…Moreover, despite some controversy still exists about whether hOCT1 is a sorafenib transporter or not, it has recently been shown that sorafenib uptake and cytotoxicity might be affected by hOCT1 gene heterogeneity in humans (Herraez et al, 2013 ). Bendamustine, a drug currently used in front line treatment of Chronic Lymphocytic Leukemia (CLL) also appears to be a hOCT1 substrate and genetic heterogeneity in CLL patients appears to account for a subset of cases with altered drug sensitivity (Arimany-Nardi et al, 2015b ). But besides gene heterogeneity, the abundance of the transporter itself might eventually contribute to drug action.…”

Section: Discussionmentioning

confidence: 99%

Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

et al. 2016

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Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level.

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“…In vitro studies showed that these and other OCT1 mutations found in PLCs, such as c.262delT (p.Cys88Alafs*16) and c.181delCGinsT (p.Arg61Serfs*10), result in lower sorafenib uptake and hence poorer induced cytotoxicity. Short non-functional SLC22A1 mRNA variants have also been detected in other malignancies, such as glioma [28] and chronic myeloid [29][30][31] and lymphocytic [32] leukemia. Moreover, not only mRNA abundance but also the correct localization of OCT1 at the plasma membrane is important for the response of HCC patients to sorafenib [33] .…”

Section: Genetic Variants In Genes Involved In Drug Uptake (Moc-1a)mentioning

confidence: 99%

Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

Alonso-Peña¹,

Sánchez-Martín²,

Sanchon-Sanchez³

et al. 2019

CDR

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Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.

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Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine uptake and cytotoxicity in chronic lymphocytic leukemia (CLL) cells

Cited by 17 publications

References 39 publications

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

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