The Role of Human Nucleoside Transporters in Cellular Uptake of 4′-Thio-β-d-arabinofuranosylcytosine and β-d-Arabinosylcytosine

Clarke, Marilyn L.; Damaraju, Vijaya L.; Zhang, Jing; Mowles, Delores; Tackaberry, Tracey; Lang, Thach; Smith, Kyla M.; Young, James D.; Tomkinson, Blake; Cass, Carol E.

doi:10.1124/mol.105.021543

Cited by 35 publications

(28 citation statements)

References 37 publications

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“…The currently used AML chemotherapeutic, cytarabine, is a nucleoside analogue known to primarily use the ent1 nucleoside transporter to enter and exit cells (9). As 6BT is a potent ent1 inhibitor, the ability of 6BT to inhibit or synergize with cytarabine-mediated leukemia cell killing was assessed.…”

Section: Resultsmentioning

confidence: 99%

Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound

Wald¹,

Vermaat

Zang

et al. 2008

Cancer Research

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As the pathophysiology of acute myelogenous leukemia (AML) involves a block of myeloid maturation, a desirable therapeutic strategy is to induce leukemic cell maturation to increase the efficacy and to avoid the side effects of traditional chemotherapeutics. Through a compound library screen, 6-benzylthioinosine (6BT) was identified as a promising differentiation-inducing agent. 6BT induces monocytic differentiation of myeloid leukemia cell lines such as HL-60 and OCI-AML3, as well as primary patient samples as evidenced by morphology, immunophenotyping, and nitroblue tetrazolium reduction. Not only can 6BT induce differentiation but a subset of AML cell lines such as MV4-11 and HNT34 instead undergo 6BT-mediated cell death. Despite inducing cell death in some leukemic cells, 6BT exhibits extremely low toxicity on several nonmalignant cells such as fibroblasts, normal bone marrow, and endothelial cells. This toxicity profile may relate to the function of 6BT as an inhibitor of the nucleoside transporter, ent1, which is thought to prevent it from entering many cell types. In contrast, 6BT likely enters at least some leukemic cell lines as shown by its requirement for phosphorylation for its differentiation activity. 6BT is also able to synergize with currently used myeloid differentiation agents such as ATRA and decitabine. Early studies indicate that the mechanism of action of this compound may involve ATP depletion that leads to growth inhibition and subsequent differentiation. Besides in vitro activity, 6BT also shows the ability to impair HL-60 and MV4-11 tumor growth in nude mice. 6BT is a promising new monocytic differentiation agent with apparent leukemic cell-specific activity. [Cancer Res 2008;68(11):4369-76]

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Section: Resultsmentioning

confidence: 99%

Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound

Wald¹,

Vermaat

Zang

et al. 2008

Cancer Research

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“…Both cytarabine and gemcitabine have chemotherapeutic applications in the CNS, and transport across the BBB and into tumor cells occurs by hENTs and/or hCNTs. Cytarabine is a permeant for hENT1 and hENT2, but is not transported by hCNTs ( Table 1) [169]. As the primary route for cytarabine entry into cells, there is substantial clinical evidence correlating hENT1 transport of cytarabine and tumor response to chemotherapy.…”

Section: Nucleoside Anticancer and Antiviral Derivativesmentioning

confidence: 99%

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

Parkinson¹,

Damaraju²,

Graham³

et al. 2011

CTMC

161

148

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Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.

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“…Thus nucleoside transporters can be the rate-limiting step in the efficacy and toxicity of nucleoside drugs. Indeed, this has been demonstrated in vitro for a number of drugs (12,30,34,49). Recently, we have also shown (33) that mitochondrial expression of hENT1 facilitates the entry of fialuridine into the mitochondria and enhances the mitochondrial toxicity of this nucleoside drug.…”

mentioning

confidence: 91%

In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta

Govindarajan¹,

Bakken²,

Hudkins³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

126

119

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To better understand the role of human equilibrative (hENTs) and concentrative (hCNTs) nucleoside transporters in physiology and pharmacology, we investigated the regional, cellular, and spatial distribution of two hCNTs (hCNT1 and hCNT2) and two hENTs (hENT1 and hENT2) in four human tissues. Using in situ hybridization and immunohistochemical techniques, we found that the duodenum expressed hCNT1 and hCNT2 mRNAs in enterocytes and hENT1 and hENT2 mRNAs in crypt cells. In these cells, the hCNT and hENT proteins were predominantly localized in the apical and lateral membrane, respectively. Hepatocytes expressed higher levels of mRNAs of hENT1, hCNT1, and hENT2 than of hCNT2 and expressed all these proteins at hepatocyte cell borders and in the cytoplasm. While the kidney expressed hCNT1 and hCNT2 mRNAs in the proximal tubules, hENT1 and hENT2 mRNAs were present in the distal tubules, glomeruli, endothelial cells, and vascular smooth muscle cells. Proximal tubules adjacent to corticomedullary junctions expressed hENT1, hCNT1, and hCNT2 mRNA. Immunolocalization studies revealed predominant localization of hCNTs in the brush-border membrane of the proximal tubular epithelial cells and hENTs in the basolateral membrane of the distal tubular epithelial cells. Chorionic villi sections of human term placenta expressed mRNAs and proteins for hENT1 and hENT2 but only mRNA for hCNT2. Immunolocalization studies showed presence of hENT1 in the brush-border membrane of the syncytiotrophoblasts. These data are critical for a better understanding of the role of nucleoside transporters in the physiological and pharmacological effects of nucleosides and nucleoside drugs, respectively.

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The Role of Human Nucleoside Transporters in Cellular Uptake of 4′-Thio-β-d-arabinofuranosylcytosine and β-d-Arabinosylcytosine

Cited by 35 publications

References 37 publications

Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound

Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound

Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain

In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta

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