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Only 3\u2032,5\u2032-cGMP significantly reduced IL-2 production. Flow cytometric analysis of apoptotic (propidium iodide\/annexin V staining) and anti-proliferative (CFSE staining) effects revealed that 3\u2032,5\u2032-cGMP concentrations &gt;\u200950\u00a0\u03bcM strongly inhibited proliferation and promoted apoptosis of HuT-78 cells (cultured in the presence of \u03b1CD3 antibody). Similar effects were observed for the positional isomer 2\u2032,3\u2032-cGMP and for 2\u2032,-GMP, 3\u2032-GMP, 5\u2032-GMP, and guanosine. By contrast, guanosine and guanosine-derived nucleotides had no cytotoxic effect on peripheral blood mononuclear cells (PBMCs) or acute lymphocytic leukemia (ALL) xenograft cells. The anti-proliferative and apoptotic effects of guanosine and guanosine-derived compounds on HuT-78 cells were completely eliminated by the nucleoside transport inhibitor NBMPR (S-(4-Nitrobenzyl)-6-thioinosine). By contrast, the ecto-phosphodiesterase inhibitor DPSPX (1,3-dipropyl-8-sulfophenylxanthine) and the CD73 ecto-5\u2032-nucleotidase inhibitor AMP-CP (adenosine 5\u2032-(\u03b1,\u03b2-methylene)diphosphate) were not protective. We hypothesize that HuT-78 cells metabolize guanosine-derived nucleotides to guanosine by yet unknown mechanisms. Guanosine then enters the cells by an NBMPR-sensitive nucleoside transporter and exerts cytotoxic effects. This transporter may be ENT1 because NBMPR counteracted guanosine cytotoxicity in HuT-78 cells with nanomolar efficacy (IC<jats:sub>50<\/jats:sub> of 25\u201330\u00a0nM). Future studies should further clarify the mechanism of the observed effects and address the question, whether guanosine or guanosine-derived nucleotides may serve as adjuvants in the therapy of cancers that express appropriate nucleoside transporters and are sensitive to established nucleoside-derived cytostatic drugs.<\/jats:p>","DOI":"10.1007\/s00210-020-01864-8","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T18:03:18Z","timestamp":1587405798000},"page":"1251-1267","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Apoptotic and anti-proliferative effect of guanosine and guanosine derivatives in HuT-78 T lymphoma cells"],"prefix":"10.1007","volume":"393","author":[{"given":"Erich H.","family":"Schneider","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Hofmeister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Solveig","family":"K\u00e4lble","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"1864_CR1","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.neuint.2013.01.019","volume":"62","author":"P Albrecht","year":"2013","unstructured":"Albrecht P, Henke N, Tien ML, Issberner A, Bouchachia I, Maher P, Lewerenz J, Methner A (2013) Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity. 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