SST0001, a Chemically Modified Heparin, Inhibits Myeloma Growth and Angiogenesis via Disruption of the Heparanase/Syndecan-1 Axis
- 15 March 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 17 (6), 1382-1393
- https://doi.org/10.1158/1078-0432.ccr-10-2476
Abstract
Purpose: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. Experimental Design: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo. Results: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. Conclusions: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma. Clin Cancer Res; 17(6); 1382–93. ©2011 AACR.Keywords
This publication has 57 references indexed in Scilit:
- Pre-clinical and clinical significance of heparanase in Ewing’s sarcomaJournal of Cellular and Molecular Medicine, 2011
- Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and ActivityPublished by Elsevier BV ,2011
- Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasisThe FEBS Journal, 2010
- Syndecan-1 Is Required for Robust Growth, Vascularization, and Metastasis of Myeloma Tumors in VivoPublished by Elsevier BV ,2009
- Syndecan-1 regulates αvβ3 and αvβ5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitorThe Journal of Experimental Medicine, 2009
- Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in MyelomaPublished by Elsevier BV ,2008
- Syndecan-1: a dynamic regulator of the myeloma microenvironmentClinical & Experimental Metastasis, 2007
- The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapyBlood, 2007
- Heparanase: a target for drug discovery in cancer and inflammationBritish Journal of Pharmacology, 2007
- Non-Anticoagulant Heparins and Inhibition of CancerPathophysiology of Haemostasis and Thrombosis, 2007