Inhibition of human equilibrative nucleoside transporters by 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine

Tang, Philip Chiu‐Tsun; Yang, Cui; Li, Rachel Wai Sum; Lee, Simon Ming‐Yuen; Hoi, Maggie Pui Man; Chan, Shun Wan; Kwan, Yiu Wa; Tse, Chung Ming; Leung, George Pak-Heng

doi:10.1016/j.ejphar.2016.07.002

Cited by 11 publications

(14 citation statements)

References 34 publications

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“…For example, the mRNA expression level for ENT2 was significantly higher in inflamed colon than noninflamed tissues of inflammatory bowel disease patients [48]. The levels of ENT2 were observed to be 2-5.5-fold higher in breast, kidney, and prostate cancer cells than in normal cells [12]. The highest expression of ENT2 is in cancers derived from digestive organ tissues because of mRNA level of ENT2 is highly expressed in the digestive system [2].…”

Section: Ent2 Localization and Expressionmentioning

confidence: 99%

“…The substrate supplies for nucleotide synthesis and maintaining the pool of intracellular nucleotides in case of reduced cellular nucleoside availability are provided by hypoxanthine. As a result, any interruption of ENT2 activity and/or expression could be detrimental to the cells by promoting the intracellular hypoxanthine conversion to xanthine and uric acid and then producing reactive oxygen species (ROS) as a by-product [12]. In addition, during muscle exercise and recovery, tissues such as skeletal muscle may take up adenosine and its metabolite inosine and hypoxanthine via ENT2 [6,9,51].…”

Section: Physiological Roles Of Ent2mentioning

confidence: 99%

“…The expression profile of hENT2 has been evaluated in several solid cancers, including gastrointestinal, breast, pancreatic, kidney, colorectal, and prostate cancers [12,42,60,77,78]. Indeed, the advanced stages in several cancers [49] including mantle cell lymphoma, hepatocellular carcinoma, and ovarian carcinoma have been correlated with the high level of ENT2 expression [49,79,80].…”

Section: Ent2 Is Associated With Cancer Progressionmentioning

confidence: 99%

“…Most of the common nucleoside transporter inhibitors such as NBMPR, dilazep, and dipyridamole are more specific for ENT1 rather than ENT2. However, 4-((4-(2-fluorophenyl) piperazin-1-yl) methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) was found to be more selective towards ENT2 than ENT1 [12]. Recently, FPMINT derivative, a modified structure of FPMINT, was also more selective to ENT2 than ENT1 when compared to its parent compound FPMINT [13].…”

Section: Introductionmentioning

confidence: 99%

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Equilibrative Nucleoside Transporter 2: Properties and Physiological Roles

Naes

Ab‐Rahim

Mazlan

et al. 2020

BioMed Research International

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Equilibrative nucleoside transporter 2 (ENT2) is a bidirectional transporter embedded in the biological membrane and is ubiquitously found in most tissue and cell types. ENT2 mediates the uptake of purine and pyrimidine nucleosides and nucleobase besides transporting a variety of nucleoside-derived drugs, mostly in anticancer therapy. Since high expression of ENT2 has been correlated with advanced stages of different types of cancers, consequently, this has gained significant interest in the role of ENT2 as a potential therapeutic target. Furthermore, ENT2 plays critical roles in signaling pathway and cell cycle progression. Therefore, elucidating the physiological roles of ENT2 and its properties may contribute to a better understanding of ENT2 roles beyond their transportation mechanism. This review is aimed at highlighting the main roles of ENT2 and at providing a brief update on the recent research.

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Section: Ent2 Localization and Expressionmentioning

confidence: 99%

Section: Physiological Roles Of Ent2mentioning

confidence: 99%

Section: Ent2 Is Associated With Cancer Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Equilibrative Nucleoside Transporter 2: Properties and Physiological Roles

Naes

Ab‐Rahim

Mazlan

et al. 2020

BioMed Research International

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“…These isoforms are distinguished by their distinct sensitivities for NBMPR; nanomolar concentrations effectively block ENT1 activity (NBMPR-sensitive), whereas ENT2 inhibition requires micromolar concentrations (NBMPR-insensitive) (Griffith and Jarvis, 1996;Griffiths et al, 1997a,b;Young et al, 2013;Huang et al, 2017). The cloning of ENT1 (Griffiths et al, 1997a) and ENT2 (Griffiths et al, 1997b;Crawford et al, 1998) established the distinct molecular identities of the NBMPR-sensitive (high affinity; ENT1) and -insensitive (low affinity; ENT2) components of equilibrative nucleoside transport in mammalian cells, and heterologous expression of cloned ENTs results in differential inhibition of transport indicative of ENT1 and ENT2 activity (Ward et al, 2000;Sundaram et al, 2001;Yao et al, 2001;Tang et al, 2016;Huang et al, 2017). These two transporters are of particular interest in studying the disposition of nucleoside reverse-transcriptase inhibitors (NRTIs) because of the structural similarity between these compounds and endogenous nucleosides.…”

Section: Introductionmentioning

confidence: 99%

Nucleoside Reverse Transcriptase Inhibitor Interaction with Human Equilibrative Nucleoside Transporters 1 and 2

et al. 2020

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Equilibrative nucleoside transporters (ENTs) transport nucleosides across the blood-testis barrier (BTB). ENTs are of interest to study the disposition of nucleoside reverse-transcriptase inhibitors (NRTIs) in the human male genital tract because of their similarity in structure to nucleosides. HeLa S3 cells express ENT1 and ENT2 and were used to compare relative interactions of these transporters with selected NRTIs. Inhibition of [ 3 H] uridine uptake by NBMPR was biphasic, with IC 50 values of 11.3 nM for ENT1 and 9.6 mM for ENT2. Uptake measured with 100 nM NBMPR represented ENT2-mediated transport; subtracting that from total uptake represented ENT1-mediated transport. The kinetics of ENT1-and ENT2-mediated [ 3 H]uridine uptake revealed no difference in J max (16.53 and 30.40 pmol cm 22 min 21 ) and an eightfold difference in K t (13.6 and 108.9 mM). The resulting fivefold difference in intrinsic clearance (J max /K t ) for ENT1-and ENT2 transport accounted for observed inhibition of [ 3 H]uridine uptake by 100 nM NBMPR. Millimolar concentrations of the NRTIs emtricitabine, didanosine, lamivudine, stavudine, tenofovir disoproxil, and zalcitabine had no effect on ENT transport activity, whereas abacavir, entecavir, and zidovudine inhibited both transporters with IC 50 values of ∼200 mM, 2.5 mM, and 2 mM, respectively. Using liquid chromatography-tandem mass spectrometry and [ 3 H] compounds, the data suggest that entecavir is an ENT substrate, abacavir is an ENT inhibitor, and zidovudine uptake is carrier-mediated, although not an ENT substrate. These data show that HeLa S3 cells can be used to explore complex transporter selectivity and are an adequate model for studying ENTs present at the BTB. SIGNIFICANCE STATEMENTThis study characterizes an in vitro model using S-[(4-nitrophenyl) methyl]-6-thioinosine to differentiate between equilibrative nucleoside transporter (ENT) 1-and ENT2-mediated uridine transport in HeLa cells. This provides a method to assess the influence of nucleoside reverse-transcriptase inhibitors on natively expressed transporter function. Determining substrate selectivity of the ENTs in HeLa cells can be effectively translated into the activity of these transporters in Sertoli cells that comprise the blood-testis barrier, thereby assisting targeted drug development of compounds capable of circumventing the blood-testis barrier.

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