PMID- 37711611 OWN - NLM STAT- MEDLINE DCOM- 20230918 LR - 20230919 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phospho-diesterase-1 (NPP1) - a promising target for the immunotherapy of cancer. PG - 1173634 LID - 10.3389/fimmu.2023.1173634 [doi] LID - 1173634 AB - INTRODUCTION: Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy. METHODS AND RESULTS: In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds' antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells. DISCUSSION: NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer. CI - Copyright (c) 2023 Lopez, Schuh, Mirza, Vaassen, Schmidt, Sylvester, Idris, Renn, Schakel, Pelletier, Sevigny, Naggi, Scheffler, Lee, Bendas and Muller. FAU - Lopez, Vittoria AU - Lopez V AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Schuh, H J Maximilian AU - Schuh HJM AD - Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, Bonn, Germany. FAU - Mirza, Salahuddin AU - Mirza S AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Vaassen, Victoria J AU - Vaassen VJ AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Schmidt, Michael S AU - Schmidt MS AD - Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, Bonn, Germany. FAU - Sylvester, Katharina AU - Sylvester K AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Idris, Riham M AU - Idris RM AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Renn, Christian AU - Renn C AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Schakel, Laura AU - Schakel L AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Pelletier, Julie AU - Pelletier J AD - Centre de Recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada. FAU - Sevigny, Jean AU - Sevigny J AD - Centre de Recherche du CHU de Quebec-Universite Laval, Quebec, QC, Canada. AD - Department de Microbiologie-Infectiologie et d'Immunologie, Faculte de Medecine, Universite Laval, Quebec, QC, Canada. FAU - Naggi, Annamaria AU - Naggi A AD - Institute for Chemical and Biochemical Research "G. Ronzoni", Milan, Italy. FAU - Scheffler, Bjorn AU - Scheffler B AD - DKFZ Division Translational Neurooncology at the West German Cancer Center (WTZ), DKTK Partner site, University Hospital Essen and German Cancer Research Center, Heidelberg, Germany. FAU - Lee, Sang-Yong AU - Lee SY AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. FAU - Bendas, Gerd AU - Bendas G AD - Pharmaceutical Institute, Pharmaceutical and Cell Biological Chemistry, University of Bonn, Bonn, Germany. FAU - Muller, Christa E AU - Muller CE AD - Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, Bonn, Germany. AD - PharmaCenter Bonn, University of Bonn, Bonn, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230829 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 9005-49-6 (Heparin) RN - 0 (Anticoagulants) RN - 0 (Heparin, Low-Molecular-Weight) SB - IM MH - Humans MH - *Heparin/pharmacology MH - Immunotherapy MH - Anticoagulants MH - Heparin, Low-Molecular-Weight/pharmacology/therapeutic use MH - *Glioma PMC - PMC10497752 OTO - NOTNLM OT - NPP1 OT - U87 glioblastoma cells OT - adenosine OT - ectonucleotidase inhibitors OT - heparin OT - immuno-oncology COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/09/15 06:43 MHDA- 2023/09/18 12:42 PMCR- 2023/01/01 CRDT- 2023/09/15 03:54 PHST- 2023/02/24 00:00 [received] PHST- 2023/07/03 00:00 [accepted] PHST- 2023/09/18 12:42 [medline] PHST- 2023/09/15 06:43 [pubmed] PHST- 2023/09/15 03:54 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1173634 [doi] PST - epublish SO - Front Immunol. 2023 Aug 29;14:1173634. doi: 10.3389/fimmu.2023.1173634. eCollection 2023.