Abstract
Almost all drugs used in anti-human immunodeficiency virus (HIV)-1 and anticancer therapies require membrane proteins to get into the cell to develop their proper activity. Nevertheless, little is known regarding the expression and activity of specific carriers involved in the uptake of these drugs in immune cells. Here, we assessed the mRNA levels, protein expression profile, and activity of the gene families SLC28 (coding for concentrative nucleoside transporters, hCNT1–3), SLC29 (equilibrative nucleoside transporters, hENT1–2), and SLC22 (organic cation transporters, hOCT1–3 and hOCTN1–2). Both hENTs and hCNT2 were abundant in primary lymphocytes, with a preferential activity of hENT1. A significant up-regulation in hENTs expression (100-fold) and activity (30-fold) was seen under stimulation of primary T lymphocytes. In contrast, monocytes, monocyte-derived macrophages (MDMs), and immature monocyte-derived dendritic cells predominantly expressed hCNT3, a functional transporter in MDMs. Finally, in immune cells, hOCTs showed a more heterogeneous expression profile and a lower activity than human nucleoside transporters (hNTs), although up-regulation of hOCTs also occurred upon lymphocyte activation. Overall, the expression and activity of most of the studied transporters emphasize their relevance in relation to anti-HIV and anticancer therapies. The identification of the transporter involved in each specific drug uptake in immune cells could help to optimize pharmacological therapeutic responses.
Footnotes
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This work has been mostly supported by Grants FIPSE 36372/03 and 36621/06, (jointly to M.P.-A. and J.M.-P.). Additional support was provided by Research Grants SAF2005-01259 (to M.P.-A.) and SAF2004-06991, Marató-TV3 021110, and the Spanish AIDS network “Red Temática Cooperativa de Investigación en Sindrome de Immune Deficiencia Adquirida (SIDA) (G03/173 and RD06/006)” (to J.M.-P.). S.P. was supported by Fundación para la Investigación y la Prevención de SIDA en España, and G.M. was supported by Grant 2005FI-00314 from Agència de Gestic d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.131482.
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ABBREVIATIONS: HIV, human immunodeficiency virus; hCNT, human concentrative nucleoside transporter; hENT, human equilibrative nucleoside transporter; hOAT, human organic anion transporter; hOCT, human organic cation transporter; hOCTN, human organic cation/zwitterion transporter; PHA, phytohemagglutinin; ddC, zalcitabine; ddI, didanosine; IL, interleukin; MDM, monocyte-derived macrophages; D-22, 1,1′-diethyl-2,2′-cyanine iodide; MDDCs, monocyte-derived dendritic cells; NBTI, nitrobenzylthioinosine; DIP, dipyridamole; MPP+, N-methyl-4-phenylpyridinium; ET, ergothioneine; GM-CSF, granulocyte/macrophage colony-stimulating factor; HRP, horseradish peroxidase; AZT, azidothymidine; TBS, Tris-buffered saline; LPS, lipopolysaccharide; PCR, polymerase chain reaction; CT, threshold cycle; mMDDC, mature MDDC; 5′-DFUR, 5′-deoxy-5-fluorouradine; Rani, ranitidine; hNT, human nucleoside transporters; DAB, 3,3′-diaminobenzidine.
- Received September 10, 2007.
- Accepted November 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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Expression and Functionality of Anti-Human Immunodeficiency Virus and Anticancer Drug Uptake Transporters in Immune Cells
