Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode

Scharrenbroich, Jessica; Kaever, Volkhard; Dove, Stefan; Seifert, Roland; Schneider, Erich

doi:10.1007/s00210-018-1582-5

Cited by 4 publications

(1 citation statement)

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“…Moreover, the pyrimidine nucleoside uridine activates adenosine receptors (Yilmaz et al 2008). Thus, the non-canonical cyclic nucleotide cUMP, which is currently discussed as a potential second messenger (Seifert et al 2015;Berrisch et al 2017;Ostermeyer et al 2018;Scharrenbroich et al 2019), may as well be exported and degraded to biologically active products. Preliminary results suggest that first-and second messenger effects of cyclic nucleotides are highly dependent on the investigated cell type (Schneider et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Apoptotic and anti-proliferative effect of guanosine and guanosine derivatives in HuT-78 T lymphoma cells

Schneider

Hofmeister

Kälble

et al. 2020

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of 100 μM of 3′,5′-cGMP, cAMP, cCMP, and cUMP as well as of the corresponding membrane-permeant acetoxymethyl esters on anti-CD3-antibody (OKT3)-induced IL-2 production of HuT-78 cutaneous T cell lymphoma (Sézary lymphoma) cells were analyzed. Only 3′,5′-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′,5′-cGMP concentrations > 50 μM strongly inhibited proliferation and promoted apoptosis of HuT-78 cells (cultured in the presence of αCD3 antibody). Similar effects were observed for the positional isomer 2′,3′-cGMP and for 2′,-GMP, 3′-GMP, 5′-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′-nucleotidase inhibitor AMP-CP (adenosine 5′-(α,β-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 50 of 25-30 nM). Future studies should further clarify the mechanism of the observed effects and address the question, whether guanosine or guanosinederived nucleotides may serve as adjuvants in the therapy of cancers that express appropriate nucleoside transporters and are sensitive to established nucleoside-derived cytostatic drugs.

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