SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.
SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.
复制标题
DOI：
10.1158/1078-0432.ccr-10-2476
复制
发表时间：
2011-03-15
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Ritchie JP;Ramani VC;Ren Y;Naggi A;Torri G;Casu B;Penco S;Pisano C;Carminati P;Tortoreto M;Zunino F;Vlodavsky I;Sanderson RD;Yang Y
Heparanase promotes myeloma growth, dissemination and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a non-anticoagulant heparin with anti-heparanase activity was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. 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. 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 down regulation 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 anti-heparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. These results provide mechanistic insight into the anti-tumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.
