Study of the effects of FPMINT on human - Title Author(s...

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Title Study of the effects of FPMINT on human equilibrative nucleoside transporters and cell growth Author(s) Tang, Chiu-tsun, Philip; Citation Tang, C. P. [ ]. (2016). Study of the effects of FPMINT on human equilibrative nucleoside transporters and cell growth. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Issued Date 2016 URL http://hdl.handle.net/10722/236584 Rights The author retains all proprietary rights, (such as patent rights) and the right to use in future works.
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Study of the effects of FPMINT on human equilibrative nucleoside transporters and cell growth Tang Chiu Tsun Philip B.Sc. (Hon.), HK A thesis submitted in partial fulfillment of the requirements for the Degree of Master of Philosophy at the University of Hong Kong August 2016
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1 Abstract of thesis entitled “Study of the effects of FPMINT on human equilibrative nucleoside transporters and cell growth” Submitted by Tang Chiu Tsun Philip for the degree of Master of Philosophy at The University of Hong Kong in August 2016 Equilibrative nucleoside transporters (ENTs) are a group of proteins which facilitate the nucleosides transport across the membrane. They control the intracellular and extracellular concentrations of physiological nucleosides such as adenosine, as well as the entry and efflux of anticancer nucleoside analogues. ENT1 plays a crucial role in cardioprotection but the physiological role of ENT2 remains unclear. Development of ENT2 - selective inhibitors can facilitate the research on ENT2 but all the commercially available inhibitors of ENTs such as nitrobenzylthioinosine and dipyridamole are ENT1 - selective. In this study, we characterized the effects of a novel compound known as 4 - ((4 - (2 - fluorophenyl)piperazin - 1 - yl)methyl) - 6 - imino - N - (naphthalen - 2 - yl) - 1,3,5 - triazin - 2 - amine (FPMINT). The results of radioactive nucleoside uptake study showed that FPMINT was an inhibitor with a higher selectivity to ENT2 than ENT1. Kinetic study showed that FPMINT inhibited the maximum velocity but had no effect on Michaelis constant of nucleoside uptake, indicating that the
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2 inhibitory effect of FPMINT was irreversible and through a non - competitive mechanism. The chemical structure of FPMINT contains a piperzine moiety, which is know to be cytotoxic. Therefore, the cytotoxic effect of FPMINT and the mechanism behind were also studied. FPMINT possessed toxic effect to cardiovascular cells such as H9c2, which is rat embryonic cardiomyoblasts. As reflected from the dihydroethidium fluorescence, FPMINT induced the production of superoxide. The origin of superoxide was mainly from mitochondria since the cytotoxic effect of FPMINT could be reversed by mitochondrial targeted superoxide inhibitor Mito - TEMPO. With the use of biochemical assay and fluorescent probe which is sensitive to mitochondrial potential change, our results showed that FPMINT increased the intracellular adenosine triphosphate level and mitochondrial membrane potential. The results of MDA assay demonstrated that FPMINT caused lipid peroxidation.
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