生物谷Bioon.com 訊 癌癥是危害人類(lèi)健康的主要因素之一,。其中肝細(xì)胞癌（HCC）死亡率在第二位，每年約有60萬(wàn)患者死于肝癌，而且發(fā)病率仍在飆升,。以抑制腫瘤血管生成而間接抑制腫瘤生長(zhǎng)不失為一種優(yōu)選方法,，但是由于機(jī)體對(duì)抗血管生成抑制劑的耐藥性，尋找高效,、低毒的抗血管抑制劑是癌癥治療的熱點(diǎn)之一,。
中國(guó)科學(xué)院上海藥物研究所糖生物學(xué)及糖化學(xué)實(shí)驗(yàn)室丁侃課題組對(duì)多糖的抗腫瘤作用機(jī)制進(jìn)行了研究。該課題組從中藥天麻中提取,、純化修飾得到多糖化合物WSS25,，發(fā)現(xiàn)該多糖化合物通過(guò)靶向骨形成蛋白BMP2及其受體，阻斷BMP/SMAD/ID1信號(hào)通路對(duì)抗血管生成進(jìn)而在體內(nèi)發(fā)揮肝癌細(xì)胞瘤生長(zhǎng)的抑制作用,。研究論文于8月2日在線(xiàn)發(fā)表在美國(guó)《生物化學(xué)雜志》(Journal of Biological Chemistry),。
在肝癌細(xì)胞中高表達(dá)的I型脫氧核糖核酸結(jié)合抑制蛋白（Id1）促進(jìn)血管生成而被認(rèn)定為很好的抗腫瘤血管生成新靶點(diǎn)。硫酸肝素蛋白聚糖（HS）通過(guò)阻止硫酸肝素-蛋白反應(yīng)從而抑制血管生成,。HS模擬物WSS25抑制血管生成,，同時(shí)完全阻斷了Id1的表達(dá)，也阻斷了BMP/Smad/Id1信號(hào)通路的表達(dá),。石英微天平分析表明WSS25與BMP2及其受體強(qiáng)烈結(jié)合,。從而有效抑制肝癌細(xì)胞在裸鼠身上移植瘤的生長(zhǎng)。因此,，WSS25是具有良好開(kāi)發(fā)前景的血管生成抑制劑,，機(jī)制的研究也為靶向性多糖癌癥治療新藥研究奠定了基礎(chǔ)。
該項(xiàng)目主要由邱宏博士完成,。研究工作得到了國(guó)家科技部,、國(guó)家自然科學(xué)基金委及中國(guó)科學(xué)院的資助。（生物谷Bioon.com）
生物谷近期特別推薦會(huì)議：
2010細(xì)胞治療研究進(jìn)展與臨床應(yīng)用前沿研討會(huì) www.Cell-therapies.net 2010年9月23日-25日天津召開(kāi)
第一屆腫瘤基礎(chǔ)和轉(zhuǎn)化醫(yī)學(xué)國(guó)際研討會(huì) www.cancerasia.org 2010年10月12日-10月15日上海召開(kāi)
凝聚社會(huì)力量 共抗癌癥--生物谷專(zhuān)訪(fǎng)中山大學(xué)腫瘤防治中心錢(qián)朝南研究員
生物谷推薦英文摘要：
JBC doi: 10.1074/jbc.M110.105544
WSS25 inhibits growth of xenografted hepatocellular cancer cells in nude mice by disrupting angiogenesis via blocking BMP/SMAD/ID1 signaling
Hong Qiu1, Bo Yang2, Zhi Chao Pei1, Zhang Zhang1 and Kan Ding1,*
The highly expressed Id1 (inhibitor of DNA binding/differentiation) protein promotes angiogenesis in HCC and is a well-established target for anti-angiogenesis therapeutic strategies. Heparan sulphate (HS) mimetics such as PI-88 can abrogate HS-protein interactions to inhibit angiogenesis. Id1 is the direct downstream effector of BMPs (Bone morphogenetic proteins), which are angiogenic and HS binding proteins. Thus, targeting BMPs by HS mimetics may inhibit angiogenesis via attenuating Id1 expression. We report here that a HS mimetic WSS25 potently inhibited the tube formation of HMEC-1 cells on Matrigel and their migration. Meanwhile, WSS25 (25 μg/mL) nearly completely blocked Id1 expression in the HMEC-1 cells as demonstrated by oligo-angiogenesis microarray analysis and further confirmed by RT-PCR and Western blotting. The BMP/Smad/Id1 signaling was also blocked by WSS25 treatment in the HMEC-1 cells. Importantly, Id1 knock-down in HMEC-1 cells caused the disruption of their tube formation on Matrigel. By employing quartz crystal microbalance (QCM) analysis, we found that WSS25 strongly bound to BMP2. Moreover, WSS25 impaired BMP2 induced tube formation of HMEC-1 cells on Matrigel and angiogenesis in Matrigel transplanted into C57BL6 mice. Furthermore, WSS25 (100 mg/kg) abrogated the growth of HCC cells xenografted in male nude mice. Immunohistochemical analysis showed that both the expression of Id1 and the endothelial cell marker CD31 were lower in the WSS25 treated tumor tissue than in the control. Therefore, WSS25 is a potential drug candidate for HCC therapy as a tumor angiogenesis inhibitor.
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China;
2 College of Pharmaceutical Sciences, Zhejiang University, China
