Emerging Roles of Nucleoside Transporters

Abstract

Since human Nucleoside Transporters (hNTs) were identified by their activity as transport systems, extensive work has been done to fully characterize them at the molecular and physiological level. Many efforts have been addressed to the identification of their selectivity for natural substrates and nucleoside analogs used to treat several diseases. hNTs belong to two different gene families, SLC28 and SLC29, encoding human Concentrative Nucleoside Transporters (hCNTs) and human Equilibrative Nucleoside Transporters (hENTs), respectively. hCNTs and hENTs are integral membrane proteins, albeit structurally unrelated. Both families share common features as substrate selectivity and often tissue localization. This apparent biological redundancy may anticipate some different roles for hCNTs and hENTs in cell physiology. Thus, hENTs may have a major role in maintaining nucleoside homeostasis, whereas hCNTs could contribute to nucleoside sensing and signal transduction. In this sense, the ascription of hCNT1 to a transceptor reinforces this hypothesis. Moreover, some evidences could suggest a putative role of hCNT2 and hCNT3 as transceptors. The interacting proteins identified for hCNT2 suggest a link to energy metabolism. Moreover, the ability of hCNT2 and hCNT3 to transport adenosine links both proteins to purinergic signaling. On the other hand, the broad selectivity transporters hENTs have a crucial role in salvage pathways and purinergic signaling by means of nucleoside pools regulation. In particular, the two new hENT2 isoforms recently described together with hENT2 seem to be key elements controlling nucleoside and nucleotide pools for DNA synthesis. This review focuses on all these NTs functions beyond their mere translocation ability.

Synthesis and Cytotoxic and Antiviral Activity Profiling of All‐Four Isomeric Series of Pyrido‐Fused 7‐Deazapurine Ribonucleosides

“…All seven nucleosides showedm oderate (Àlog Papp 5-6 cm s À1 )o rl ow ability (Àlog Papp > 6cms À1 )t od iffuse across an artificial cellular membrane in the parallel artificial membrane permeabilitya ssay (PAMPA), suggesting alternative intracellular transport mechanism, probably involving nucleoside transporters. [34] The Caco- 2a nd MDCK-MDR1 permeability assays are established models of intestinal [35] and blood-brain barriers, respectively. [36] Studied compounds showed low (Papp AB < 5 10 À6 cm s À1 )o rmoderate (Papp AB 5-20 10 À6 cm s À1 )p robability of intestinal absorption and to cross blood-brain barriers (Papp AB < 10 10 À6 cm s À1 CNS À;P app AB > 10 10À6cms À1 CNS +).…”

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

“…One of the main steps for a drug to exert its cytotoxicity, as for other nucleoside analogs, is the uptake into the cell. This is mediated by the human equilibrative nucleoside transporter (hENT) and the human concentrative nucleoside transporter (hCNT) family [19]. An inhibitor of ENT1, dipyridamole, reduced sensitivity against RX-3117, indicating that hENT1 was responsible for uptake of the drug (similarly to gemcitabine), possibly excluding other transporters [12].…”

Synthesis and Evaluation of the Antitumor Properties of a Small Collection of PtII Complexes with 7‐Deazaadenosine as Scaffold

“…Such compounds have been designed to induce a synergistic effect between the platinum and biomolecule activities, even if the properties of such a composite molecule are not predictable because each active moiety can influence the pharmacological behavior of the other . In this context, nucleosides and nucleotides represent an attractive category of molecules for conjugation to drugs, due to the presence of complex systems of protein transporters on cellular membranes that can recognize and internalize them . Furthermore, considering that many nucleosides and nucleotides are effective drugs against viral diseases and cancers, as well as playing key roles in the regulation of cellular processes and in signal transduction, their conjugation to a reactive platinum unit could produce molecules with interesting biological properties.…”