Sulfated Polysaccharides from Macroalgae Are Potent Dual Inhibitors of Human ATP-Hydrolyzing Ectonucleotidases NPP1 and CD39

Marine Drugs

Jean Sévigny¹  Julie Pelletier¹  MichaelS. Schmidt²  Gerd Bendas²  H.J. Maximilian Schuh²  Sang-Yong Lee³  ChristaE. Müller³  Salahuddin Mirza³  Vittoria Lopez³  Laura Schäkel³  Christian Renn³  Susanne Alban⁴ 

[1] Centre de Recherche du CHU de Québec—Université Laval, Québec City, QC G1V 4G2, Canada;Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, 24118 Kiel, Germany;

关键词: adenosine;    CD39;    ectonucleotidase inhibitors;    fucoidan;    immuno-oncology;    NPP1;   

DOI  :  10.3390/md19020051

来源: DOAJ

【 摘 要 】

Extracellular ATP mediates proinflammatory and antiproliferative effects via activation of P2 nucleotide receptors. In contrast, its metabolite, the nucleoside adenosine, is strongly immunosuppressive and enhances tumor proliferation and metastasis. The conversion of ATP to adenosine is catalyzed by ectonucleotidases, which are expressed on immune cells and typically upregulated on tumor cells. In the present study, we identified sulfopolysaccharides from brown and red sea algae to act as potent dual inhibitors of the main ATP-hydrolyzing ectoenzymes, ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39), showing nano- to picomolar potency and displaying a non-competitive mechanism of inhibition. We showed that one of the sulfopolysaccharides tested as a representative example reduced adenosine formation at the surface of the human glioblastoma cell line U87 in a concentration-dependent manner. These natural products represent the most potent inhibitors of extracellular ATP hydrolysis known to date and have potential as novel therapeutics for the immunotherapy of cancer.

【 授权许可】

Unknown