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cells and cells of the tumor microenvironment and functions to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors that support tumor growth. Heparanase expression is upregulated in human carcinomas, sarcomas, and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter postoperative survival of cancer patients, and encouraging the development of heparanase inhibitors as anti-cancer drugs. Among these are heparin\/HS mimetics, the only heparanase-inhibiting compounds that are being evaluated in clinical trials. We have synthesized dicarboxylated oxy-heparins (DCoxHs) containing three carboxylate groups per split residue (DC-Hep). The resulting lead compound (termed XII) was upscaled, characterized, and examined for its effectiveness in tumor models. Potent anti-tumorigenic effects were obtained in models of pancreatic carcinoma, breast cancer, mesothelioma, and myeloma, yielding tumor growth inhibition (TGI) values ranging from 21 to 70% and extending the survival time of the mice. Of particular significance was the inhibition of spontaneous metastasis in an orthotopic model of breast carcinoma following resection of the primary tumor. It appears that apart from inhibition of heparanase enzymatic activity, compound XII reduces the levels of heparanase protein and inhibits its cellular uptake and activation. Heparanase-dependent and -independent effects of XII are being investigated. Collectively, our pre-clinical studies with compound XII strongly justify its examination in cancer patients.<\/jats:p>","DOI":"10.3390\/cells13030211","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T04:35:40Z","timestamp":1706070940000},"page":"211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A New Synthesized Dicarboxylated Oxy-Heparin Efficiently Attenuates Tumor Growth and Metastasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Li","family":"Li","sequence":"first","affiliation":[{"name":"Shenzhen Hepalink Pharmaceutical Group Co., Ltd., Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1049-270X","authenticated-orcid":false,"given":"Uri","family":"Barash","sequence":"additional","affiliation":[{"name":"Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neta","family":"Ilan","sequence":"additional","affiliation":[{"name":"Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malik","family":"Farhoud","sequence":"additional","affiliation":[{"name":"Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Vlodavsky","sequence":"additional","affiliation":[{"name":"Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa 3525422, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology, SciLifeLab, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-3-030-34521-1_7","article-title":"Heparanase: Cloning, Function and Regulation","volume":"1221","author":"Gaskin","year":"2020","journal-title":"Adv. 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