Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

Abstract

Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters.

Molecular Basis of Nucleobase Transport Systems in Mammals

“…However, for effective therapy using these drugs, it is important to elucidate the role of each transporter in purine salvage, in addition to documenting the alterations in their expression and functionality under different physiological and pathological conditions. Because the expression of ENT1 can be used as an effective biomarker for the diagnosis and prognosis of diseases such as cancer and the prediction of drug efficacy, 72) it could be applicable to diseases and chemotherapies involving nucleobase transporters. The molecular basis of pyrimidine nucleobase transport systems remains unclear, and its elucidation is expected in the future.…”

Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

“…hENT4, also known as PMAT, is uniquely selective for adenosine and also transports a variety of organic cations [16][17][18][19][20]. Some nucleosidederived drugs can also interact with and be translocated by members of the SLC22 gene family, which include organic anion transporters (OATs), organic cation transporters (OCTs) and organic carnitine and zwitterion transporters (OCTNs) [9,[21][22][23][24][25].…”

“…In humans, two solute carrier gene families (SLC28 and SLC29) are foremost responsible for the uptake of nucleosides and nucleoside analogues into cells [7][8][9][10][11]. The SLC28 human concentrative nucleoside transporter (hCNT) family contains three members that mediate unidirectional transport of nucleosides into cells against their concentration gradient driven by a downward sodium…”

Localization and Expression of Nucleoside Transporters ENT1 and ENT2 in Polar Cells of Intestinal Epithelium

“…Many anti-tumor and anti-viral drugs are represented by cytostatics that impair viral DNA replication and division of cancer cells. Many of these drugs are anti-metabolites, synthetic analogs of purines and pyrimidines; their transport is provided by native transporters: equilibrium (ENT) and concentrating (CNT) nucleoside transporters [13].At the same time, these proteins demonstrate wide substrate specifi city for purine and pyrimidine nucleosides and nitrogenous bases, which makes diffi cult their identifi cation and description at the functional level. ENT1 and ENT2 transportes are characterized by the ability to transfer purine base hypoxanthine [15].…”

“…Many anti-tumor and anti-viral drugs are represented by cytostatics that impair viral DNA replication and division of cancer cells. Many of these drugs are anti-metabolites, synthetic analogs of purines and pyrimidines; their transport is provided by native transporters: equilibrium (ENT) and concentrating (CNT) nucleoside transporters [13].…”