Molecular biology and regulation of nucleoside and nucleobase transporter proteins in eukaryotes and prokaryotes

Cabrita, Miguel A.; Baldwin, Stephen A.; Young, James D.; Cass, Carol E.

doi:10.1139/o02-153

Cited by 79 publications

(84 citation statements)

References 128 publications

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“…1C). hENT1 70 -YFP and hENT1 34 -YFP, showed no mitochondrial localization and instead showed diffuse localization in the cytoplasm similar to that observed for MDCK cells expressing the YFP vector alone (mock cells; data not shown). These data suggested that amino acid residues 71-74 of hENT1 contained the mitochondrial targeting signal of hENT1.…”

Section: Mitchondrial Localization Of Truncated and Mutated Hent1-yfpsupporting

confidence: 73%

Identification of the Mitochondrial Targeting Signal of the Human Equilibrative Nucleoside Transporter 1 (hENT1)

Lee

Lai

Zhang

et al. 2006

Journal of Biological Chemistry

104

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We have previously shown that the human equilibrative nucleoside transporter 1 (hENT1) is expressed and functional in the mitochondrial membrane and that this expression enhances the mitochondrial toxicity of the nucleoside drug, fialuridine ( The human nucleoside transporter, hENT1, 2 plays an important role in modulating the physiological activity of nucleosides and in the transport of many therapeutic nucleoside drugs used in the treatment of cancer (e.g. 5-fluorouridine) and viral diseases (e.g. ribavirin) (2). hENT1 is an equilibrative nucleoside transporter that is ubiquitously expressed (3). Two additional members of the equilibrative nucleoside transporter family have been identified, hENT2 and hENT3 (4, 5). hENT2 is expressed in a selective number of tissues, such as the muscle (3), whereas hENT3 appears to be an intracellular transporter, expressed primarily in the lysosomes (5). We have recently reported that hENT1 is also functionally present in intracellular compartments, specifically in the mitochondrial membrane (1). In addition, we have shown that the presence of hENT1 on the mitochondrial membrane facilitates the entry of fialuridine (FIAU) into the mitochondria, where it is phosphorylated to produce its mitochondrial toxicity.FIAU is a uridine analog that was developed for treatment of hepatitis B. Administration of this antiviral nucleoside to 15 patients with hepatitis B resulted in severe multisystem toxicity, due to mitochondrial damage, including fatal hepatotoxicity, pancreatitis, neuropathy, or myopathy (6). Among seven patients showing severe FIAU-mediated hepatotoxicity, five died, and two survived only after emergency liver transplant (6). hENT1, expressed in the mitochondrial membrane, facilitates the entry of the hydrophilic FIAU (1). Once in the mitochondria, FIAU is metabolized by thymidine kinase 2, a mitochondrial specific enzyme, to the monophosphate that is the rate-limiting step in the formation of the triphosphate (TP), a potent inhibitor of mitochondrial DNA polymerase-␥ (7). The mitochondrial hepatotoxicity of FIAU is widely accepted to be due to inhibition by FIAU-TP of the mitochondrial DNA polymerase ␥, resulting in depletion of mitochondrial DNA and cell death (8 -10).Interestingly, the lethal mitochondrial toxicity of FIAU observed in the clinic was not predicted from preclinical toxicity studies in rodents (rats or mice), even at doses that were 1,000-fold of those used in the human study (8,(11)(12)(13). This lack of predictive accuracy is troubling and important as the rodents are extensively used in drug development to predict human toxicity. These preclinical data on FIAU toxicity raise an important question. What is the mechanistic basis for this dramatic interspecies difference in FIAU toxicity? Understanding the mechanistic basis of the interspecies differences in FIAU toxicity will guide the use of appropriate species for future development of nucleoside drugs, including for preclinical toxicity studies. The lack of hepatotoxicity of FIAU in the rodents canno...

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Section: Mitchondrial Localization Of Truncated and Mutated Hent1-yfpsupporting

confidence: 73%

Identification of the Mitochondrial Targeting Signal of the Human Equilibrative Nucleoside Transporter 1 (hENT1)

Lee

Lai

Zhang

et al. 2006

Journal of Biological Chemistry

104

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“…Important structural determinants for recognition of nucleosides by membrane transporters and clinically used nucleoside drugs and resulting resistance mechanisms are reviewed. The reader is referred to recently published review articles on the molecular structure and function of NT proteins and their role in drug resistance (Mackey et al, 1998a;Baldwin et al, 1999;Vickers et al, 2000;Cabrita et al, 2002;Clarke et al, 2002).…”

Section: Human Nucleoside Transportersmentioning

confidence: 99%

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

et al. 2003

Self Cite

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The clinical efficacy of anticancer nucleoside drugs depends on a complex interplay of transporters mediating entry of nucleoside drugs into cells, efflux mechanisms that remove drugs from intracellular compartments and cellular metabolism to active metabolites. Nucleoside transporters (NTs) are important determinants for salvage of preformed nucleosides and mediated uptake of antimetabolite nucleoside drugs into target cells. The focus of this review is the two families of human nucleoside transporters (hENTs, hCNTs) and their role in transport of cytotoxic chemotherapeutic nucleoside drugs. Resistance to anticancer nucleoside drugs is a major clinical problem in which NTs have been implicated. Single nucleotide polymorphisms (SNPs) in drug transporters may contribute to interindividual variation in response to nucleoside drugs. In this review, we give an overview of the functional and molecular characteristics of human NTs and their potential role in resistance to nucleoside drugs and discuss the potential use of genetic polymorphism analyses for NTs to address drug resistance.

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“…Under normal conditions, adenosine is mainly generated at the intracellular level from S-adenosylhomocysteine by Sadenosylhomocysteine hydrolase and transported across cell membranes via purine transporters [29]. Level of adenosine in extracellular environment is controlled by nucleoside or purine transporters [30,31]. These purine transporters are divided into two main categories [32]: (1) equilibrative purine or nucleoside transporters, transporting nucleosides in/out, depending on the concentration of adenosine and (2) concentrative purine or nucleoside transporters, facilitating intracellular influx of adenosine against the concentration gradient.…”

Section: Adenosine As a Sensor For Inflammationmentioning

confidence: 99%

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Kumar

2012

Purinergic Signalling

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Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

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Molecular biology and regulation of nucleoside and nucleobase transporter proteins in eukaryotes and prokaryotes

Cited by 79 publications

References 128 publications

Identification of the Mitochondrial Targeting Signal of the Human Equilibrative Nucleoside Transporter 1 (hENT1)

Identification of the Mitochondrial Targeting Signal of the Human Equilibrative Nucleoside Transporter 1 (hENT1)

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

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