May-June 2011, Volume 8, Issue 3
Heparin: Everything Old is New Again
Published on: May 01, 2011
Drs. Wang and Linenberger indicated no relevant conflicts of interest.
Ritchie JP, Ramani VC, Ren Y, et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res. 2011. [Epub ahead of print]
Poli M, Girelli D, Campostrini N, et al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood. 2011;117:997-1004.
Heparin, a tissue-derived glycosaminoglycan (GAG), has been widely used as a standard anticoagulant for more than 40 years. A pentasaccharide sulfation sequence within the heparin polymer binds antithrombin and mediates the anticoagulant activity. Heparin also possesses non-anticoagulant properties, and these relate to the binding, immobilization, and/or activation of proteins, growth factors, chemokines, and matrix metalloproteinases (MMPs). These alternative functions have triggered investigations of heparin-based agents in cancer and inflammation. Two recent reports explore these pleiotropic mechanisms of heparin and heparin derivatives and suggest novel therapeutic applications.
A study by Dr. Ritchie et al. from University of Alabama Birmingham was prompted by the knowledge that heparanase is highly expressed in multiple myeloma (MM) and other tumor microenvironments, where it promotes growth and invasion by enhancing growth factor expression and stimulating the shedding of heparan sulfate proteoglycan syndecan-1. Using a number of murine xenograft models of MM, the team evaluated the effects of SST0001, a modified non-anticoagulant heparin with potent anti-heparanase activity. They observed that SST0001 significantly inhibits MM growth without associated adverse effects and that combination with dexamethasone augments tumor suppression and overcomes dexamethasone resistance. SST0001 reduced intratumoral CD34+ vascularity and extracellular HGF and VEGF levels, and inhibited MMP-9 expression and syndecan-1 shedding. Collectively, these data suggest that the anti-heparanase activity of SST0001 prevents downstream activation MMP9, syndecan-1 release, and other growth promoting factors that stimulate angiogenesis and myeloma progression.
Dr. Poli et al. from Brescia, Italy, investigated whether heparin might affect liver hepcidin expression, because cell surface heparan sulfate proteoglycans are known to modulate bone morphogenetic protein (BMP) activities and BMP signaling regulates hepcidin expression. Unfractionated heparin (UFH) was found to strongly inhibit hepcidin mRNA expression in cultured HepG2 liver cells, whereas low molecular-weight heparin (LMWH) had a modest effect and the pentasaccharide anticoagulant fondaparinux had minimal effect. UFH appears to act by sequestering extracellular BMPs (mainly BMP6), which prevent BMP6 signaling through pSMAD1/5/8 and downstream induction of hepcidin expression. Treating mice with UFH lowered basal levels of liver pSMAD1/5/8 protein and hepcidin mRNA, reduced splenic iron content, and increased serum iron levels. An exploratory study of five patients receiving prophylactic LMWH for serious infection or medical illness revealed decreased levels of serum hepcidin and C-reactive protein at 20 hours and subsequent increases in serum iron and transferrin saturation.
If the observations of Dr. Ritchie et al. are confirmed in additional studies, SST0001 could soon move to phase I trials of patients with myeloma or other heparanase-producing tumors. The observations by Dr. Poli et al. are intriguing and suggest that rationally designed, non-anticoagulant heparin oligosaccharides with BMP-modulating activities might be useful for anemia of inflammation and other conditions with hepcidin overexpression. On a more global level, these reports complement a large body of work with other non-anticoagulant heparin derivatives, heparan sulfate-based drugs, GAG mimetics, and glycan-based inhibitors developed for metabolic, infectious, inflammatory, and malignant disorders and tissue regeneration.1,2 It is enlightening to realize that our “age-old” friend heparin has played a major role in the understanding of glycobiology in health and disease and has facilitated drug discovery in a number of exciting directions.
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- Gandhi NS, Mancera RL. Heparin/heparan sulphate-based drugs. Drug Discov Today. 2010;15:1058-1069.
- Brown JR, Crawford BE, Esko JD.Glycan antagonists and inhibitors: a fount for drug discovery. Crit Rev Biochem Mol Biol. 2007;42:481-515.