11月1日出版的Cancer Research发表了中科院上海药物所谢欣研究组和第二军医大学药学院海洋药物研究中心易杨华研究组的最新研究成果，他们揭示了海洋天然产物Bryostatins在抗肿瘤转移方面的作用机理。
Bryostatins是从海洋生物草苔虫中分离得到的一类大环内酯类化合物，有近20个结构类似物。研究显示，Bryostatins对肿瘤生长、转移及血管新生都有抑制作用，其中Bryostatin-1已经在美国进入临床研究，是极有希望的新型抗癌药物，然而其抗癌机理，尤其是抗肿瘤转移的机理目前尚不清楚。
据科研人员介绍，趋化因子是一类诱导免疫细胞定向运动的细胞因子，其受体均为G蛋白偶联受体。近年来的研究证明，趋化因子SDF-1及其受体CXCR4在肿瘤转移方面也起着重要的作用，多种肿瘤细胞的表面均高表达CXCR4。谢欣研究组的硕士研究生何幸等发现，Bryostatins可以抑制SDF-1/CXCR4介导的细胞趋化运动及细胞内钙离子浓度变化，而这种抑制并非通过直接阻断SDF-1与其受体CXCR4的相互作用。进一步研究发现，Bryostatins可以引起CXCR4的脱敏及内吞，造成SDF-1/CXCR4信号转导的中止，而这一受体的脱敏及内吞是通过激活PKC来介导的。
该项研究得到了自然科学基金委、科技部、上海市科委及中科院的支持。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
