11月1日出版的Cancer Research發(fā)表了中科院上海藥物所謝欣研究組和第二軍醫(yī)大學(xué)藥學(xué)院海洋藥物研究中心易楊華研究組的最新研究成果，他們揭示了海洋天然產(chǎn)物Bryostatins在抗腫瘤轉(zhuǎn)移方面的作用機(jī)理,。
Bryostatins是從海洋生物草苔蟲中分離得到的一類大環(huán)內(nèi)酯類化合物,，有近20個(gè)結(jié)構(gòu)類似物。研究顯示,，Bryostatins對(duì)腫瘤生長,、轉(zhuǎn)移及血管新生都有抑制作用，其中Bryostatin-1已經(jīng)在美國進(jìn)入臨床研究,，是極有希望的新型抗癌藥物,，然而其抗癌機(jī)理，尤其是抗腫瘤轉(zhuǎn)移的機(jī)理目前尚不清楚,。
據(jù)科研人員介紹,，趨化因子是一類誘導(dǎo)免疫細(xì)胞定向運(yùn)動(dòng)的細(xì)胞因子，其受體均為G蛋白偶聯(lián)受體,。近年來的研究證明,，趨化因子SDF-1及其受體CXCR4在腫瘤轉(zhuǎn)移方面也起著重要的作用，多種腫瘤細(xì)胞的表面均高表達(dá)CXCR4,。謝欣研究組的碩士研究生何幸等發(fā)現(xiàn),，Bryostatins可以抑制SDF-1/CXCR4介導(dǎo)的細(xì)胞趨化運(yùn)動(dòng)及細(xì)胞內(nèi)鈣離子濃度變化,，而這種抑制并非通過直接阻斷SDF-1與其受體CXCR4的相互作用。進(jìn)一步研究發(fā)現(xiàn),，Bryostatins可以引起CXCR4的脫敏及內(nèi)吞,，造成SDF-1/CXCR4信號(hào)轉(zhuǎn)導(dǎo)的中止，而這一受體的脫敏及內(nèi)吞是通過激活PKC來介導(dǎo)的,。
該項(xiàng)研究得到了自然科學(xué)基金委,、科技部、上海市科委及中科院的支持,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Research 68, 8678-8686, November 1, 2008. doi: 10.1158/0008-5472.CAN-08-0294
Bryostatin-5 Blocks Stromal Cell–Derived Factor-1 Induced Chemotaxis via Desensitization and Down-regulation of Cell Surface CXCR4 Receptors
Xing He1, Liyan Fang1, Jue Wang1, Yanghua Yi2, Shuyu Zhang2 and Xin Xie1
1 National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate University of the Chinese Academy of Sciences; 2 Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, China
The chemokine receptor CXCR4 and its ligand, stromal cell–derived factor-1 (SDF-1), play important roles in hematopoiesis regulation, lymphocyte activation, and trafficking, as well as in developmental processes, including organogenesis, vascularization, and embryogenesis. The receptor is also involved in HIV infection and tumor growth and metastasis. Antagonists of CXCR4 have been widely evaluated for drugs against HIV and tumors. In an effort to identify novel CXCR4 antagonists, we screened a small library of compounds derived from marine organisms and found bryostatin-5, which potently inhibits chemotaxis induced by SDF-1 in Jurkat cells. Bryostatin-5 is a member of the macrolactones, and its analogue bryostatin-1 is currently being evaluated in clinical trials for its chemotherapeutic potential. The involvement of bryostatins in the SDF-1/CXCR4 signaling process has never been reported. In this study, we found that bryostatin-5 potently inhibits SDF-1–induced chemotaxis but does not affect serum-induced chemotaxis. Further studies indicate that this inhibitory effect is not due to receptor antagonism but rather to bryostatin-5–induced receptor desensitization and down-regulation of cell surface CXCR4. We also show that these effects are mediated by the activation of conventional protein kinase C.
