Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells

Cano-Soldado, Pedro; Molina‐Arcas, Míriam; Algueró, Berta; Larráyoz, Ignacio M.; Lostao, M. P.; Grandas, Anna; Casado, F. Javier; Pastor‐Anglada, Marçal

doi:10.1016/j.bcp.2007.10.005

Cited by 22 publications

(25 citation statements)

References 29 publications

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“…On the other hand, high expression of a particular hCNT-type transporter protein could promote drug-induced cytotoxicity if patients were treated with suitable hCNT substrates. At present, in vitro observations suggest that hCNT1 confers sensitivity on pyrimidine-derived nucleoside drugs in a variety of cell systems [45,49,50].…”

Section: Concentrative Transportersmentioning

confidence: 99%

Pharmacogenetics and pharmacoepigenetics of gemcitabine

et al. 2009

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Gemcitabine (2',2'-difluoro 2'deoxycytidine, dFdC) is an analog of cytosine with distinctive pharmacological properties and a wide antitumor-activity spectrum. The pharmacological characteristics of gemcitabine are unique because two main classes of genes are essential for its antitumor effects: membrane transporter protein-coding genes, whose products are responsible for drug intracellular uptake, as well as enzyme-coding genes, which catalyze its activation and inactivation. The study of the pharmacogenetics and pharmacoepigenetics of these two gene classes is greatly required to optimize the drug's therapeutic use in cancer. This review aims to provide an update of genetic and epigenetic bases that may account for interindividual variation in therapeutic outcome exhibited by gemcitabine.

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Section: Concentrative Transportersmentioning

confidence: 99%

Pharmacogenetics and pharmacoepigenetics of gemcitabine

et al. 2009

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“…The human equilibrative nucleoside transporter 1 (hENT1), the most abundant and widely distributed plasma membrane nucleoside transporter in human cells, is a member of these proteins and mediates cellular entry of gemcitabine, cytarabine, and fludarabine (Giovannetti et al, 2006b;Zhang et al, 2007). In fact deficiency in hENT1 confers resistance to toxicity and efficacy of these drugs in many in vitro models of hematologic (Tallman, 2005;Cai et al, 2008;Lai et al, 2008) and solid tumors (Mackey et al, 1998;Seve et al, 2005;Cano-Soldado et al, 2008). Kinetic studies of human cell lines with defined nucleoside transporter processes have demonstrated that gemcitabine intracellular uptake is mediated greatly by hENT1 (Mackey et al, 1998(Mackey et al, , 1999.…”

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confidence: 97%

Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer

Santini

Vincenzi

Fratto

et al. 2010

Journal Cellular Physiology

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Nucleoside transporter proteins are specialized proteins that mediate the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a member of these proteins and mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. We investigated the immunohistochemical expression of hENT in tumor samples from 111 patients with resected gastric adenocarcinoma, correlating these data with clinical parameters and disease outcomes. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant or neoadjuvant program. On univariate survival analysis, the hENT1 expression was associated with overall survival (OS) and disease free survival (DFS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.021) and a shorter DFS (P = 0.033). Considering only the node positive patients, higher hENT levels were associated with significantly shorter median DFS (21.7 months; 95% CI 11.1-32.4) compared with patients with low expression of hENT1. The hENT1 expression was defined, in the lymph-node positive patients, as an independent prognostic factor (P = 0.019). Furthermore, considering only patients with diffuse or mixed tumors and lymph-node positive, the expression of hENT1 was strongly related with DFS and OS. Immunohistochemistry for the hENT1 protein carries prognostic information in patients with resected gastric cancer and holds promise as a predictive factor in chemotherapy decisions.

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“…[36] Thus, we have recently engineered MCF7 cells to express hCNT1 and, under conditions of hENT1 inhibition, hCNT1 function is sufficient to maintain the transcriptomic and cytotoxic response associated with 5 DFUR treatment. [37] Thus, NT patterns rather than single NT proteins might modulate the therapeutic performance of most nucleoside-derived drugs. This highlights the need of clinical approaches in which several biomarkers of nucleotide metabolism (not only transporters but also enzymes) will have to be analyzed as putative predictors of drug sensitivity, thus allowing individualized therapies.…”

Section: Pharmacological Roles Of Nt Proteinsmentioning

confidence: 99%

Physiological and Pharmacological Roles of Nucleoside Transporter Proteins

Molina‐Arcas

Trigueros-Motos

Casado

et al. 2008

Nucleosides, Nucleotides and Nucleic Acids

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Nucleoside transporter proteins, CNT and ENT, encoded by gene families SLC28 and SLC29, respectively, mediate the uptake of natural nucleosides (among them adenosine) and are major routes of entry for a variety of nucleoside analogs used in anticancer and antiviral therapies. Expression of NT proteins is apparently redundant in most cell types, and the elucidation of their particular physiological roles still remains elusive. Moreover, transporter-mediated uptake of nucleoside-derived anticancer drugs is crucial for the pharmacogenomic response triggered by these molecules in tumor cells. This review focuses on recent data demonstrating that nucleoside transporters, particularly CNTs, can play physiological roles other than salvage, whereas particular NT isoforms can significantly contribute to the transcriptomic response triggered by nucleoside analogs in cancer cells.

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Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells

Cited by 22 publications

References 29 publications

Pharmacogenetics and pharmacoepigenetics of gemcitabine

Pharmacogenetics and pharmacoepigenetics of gemcitabine

Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer

Physiological and Pharmacological Roles of Nucleoside Transporter Proteins

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