Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia

Calotti, Paula Fernández; Galmarini, Carlos M.; Cañones, Cristian; Gamberale, Romina; Sáenz, Daniel A.; Avalos, Julio Sanchez; Chianelli, Mónica S.; Rosenstein, Ruth E.; Giordano, Mirta

doi:10.1016/j.bcp.2007.10.017

Cited by 18 publications

(13 citation statements)

References 46 publications

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“…The equilibrative transporter protein hENT1 is rapidly modulated by a PKC-dependent mechanism that likely involves activation of transporters already present at the plasma membrane (9,33). Regarding CNTs, we have previously shown that CNT2 is under purinergic control in liver cells (22), and its insertion into the plasma membrane is also modulated by bile acids (34).…”

Section: Discussionmentioning

confidence: 99%

“…CLL cells express hENT1, hENT2, hCNT2, and hCNT3 mRNA, although most of the biological activity responsible for Flu uptake is associated with ENT-type transporters (8,9). Interestingly, Flu-resistant populations of CLL have been reported to express high levels of cytosolic hCNT3 protein, without detectable hCNT3-related plasma membrane transport activity (10,11).…”

mentioning

confidence: 99%

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All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

Fernández-Calotti

Pastor‐Anglada

2010

Journal of Biological Chemistry

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Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. The aim of our study was to identify agents and mechanisms capable of promoting hCNT3 trafficking to the plasma membrane. Here, we report that all-transretinoic acid (ATRA), currently used in the treatment of acute promyelocytic leukemia (APL), increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of transforming growth factor (TGF)-␤1, which is transcriptionally activated by ATRA in a p38-dependent manner. TGF-␤1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

Fernández-Calotti

Pastor‐Anglada

2010

Journal of Biological Chemistry

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“…(Blum , et al 2007) No such reductions in global DNA methylation or increases in selected gene mRNA expression occurred with similar doses of decitabine in CLL and NHL patients. One possible reason for the lack of effectiveness of decitabine in the treatment of CLL is low expression of the hENT1 transporter responsible for the cellular uptake decitabine,(Fernandez Calotti , et al 2008, Marce , et al 2006) as compared to more proliferative diseases such as AML or mantle cell lymphoma. In other studies, hENT1 expression and/or function have been related to decitabine sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: dose‐limiting myelosuppression without evidence of DNA hypomethylation

Blum¹,

Liu

Lucas

et al. 2010

Br J Haematol

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SummaryTargeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non‐Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B‐cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1–3 cycles of decitabine. Dose‐limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m2 per d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m2 per d days 1–10 without DLT; however, re‐expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5‐day decitabine schedule was examined. With 15 mg/m2 per d decitabine days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3–4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome‐wide methylation or in target gene re‐expression. In conclusion, dose‐limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re‐expression in CLL and NHL.

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“…Furthermore, although IL-4-treated CLL cells exhibited high levels of hENT1, no evidence of increased hENT1 activity was found, suggesting that this newly synthesized hENT1 could be in a plasma membrane but in an inactive form. [95] This increased hENT1 protein became active when, after the incubation with IL-4, acute PKC stimulation (short term, high dose) was performed. Moreover, the induced hENT1 activity correlated with an increase in fludarabine cytotoxicity in these CLL cells ex vivo.…”

Section: Regulated Nucleoside Transport In Cllmentioning

confidence: 99%

Translocation of Nucleoside Analogs Across the Plasma Membrane in Hematologic Malignancies

Fernández-Calotti

Colomer

Pastor‐Anglada

2011

Nucleosides, Nucleotides and Nucleic Acids

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Nucleoside analogs are currently used in the treatment of various hematologic malignancies due to their ability to induce apoptosis of lymphoid cells. For nucleoside-derived drugs to exert their action, they must enter cells via nucleoside transporters from two gene families, SLC28 and SLC29 (CNT and ENT, respectively). Once inside the cell, these drugs must be phosphorylated to their active forms. In contrast, some members of the ATP-binding cassette (ABC) protein family have been identified as responsible for the efflux of the phosphorylated forms of these nucleoside-derived drugs. Here, we review the main nucleoside analogs used in hematologic malignancies and focus especially on those that are currently used in chronic lymphocytic leukemia (CLL). Moreover, we discuss the pharmacological profile of the nucleoside transporters, which determines the bioavailability of and cell sensitivity to these nucleoside-derived drugs. We also discuss the expression of nucleoside transporters and their activities in CLL as well as the possibility of modulating these transporter activities as a means of modulating intracellular drug availability and, consequently, responsiveness to therapy.

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Modulation of the human equilibrative nucleoside transporter1 (hENT1) activity by IL-4 and PMA in B cells from chronic lymphocytic leukemia

Cited by 18 publications

References 46 publications

All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: dose‐limiting myelosuppression without evidence of DNA hypomethylation

Translocation of Nucleoside Analogs Across the Plasma Membrane in Hematologic Malignancies

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