上海药物研究所俞强课题组在日前出版的最新一期的肿瘤研究权威杂志Cancer Research上发表文章，阐述治疗肿瘤的中药狼毒中有效成分的抗肿瘤作用新机理。
据悉，中药狼毒在中国被广泛应用于治疗肿瘤，其中有多种成分被发现有抗肿瘤的功能。但对这些化合物的作用靶点和作用机理缺乏深入的了解。俞强课题组发现狼毒中的二萜类化合物HJB直接作用于致癌基因JAK家族激酶。JAK激酶目前是众多国际制药企业的重要药物靶点，多家公司在寻找针对JAK激酶的抗肿瘤和抗炎症药物。俞强课题组发现，狼毒中的HJB类化合物和其它JAK抑制剂不同，是通过共价键的形式作用于该家族蛋白的一个新区域。该发现为研发JAK抑制剂提供了一个新的方向，同时也为中草药治疗癌症提供了理论和实验基础。该项工作主要由博士研究生王颖完成。上海药物所秦国伟课题组参加了化合物的制备工作。(生物谷Bioon.com)
生物谷推荐原始出处：
Cancer Research 69, 7302, September 15, 2009.doi: 10.1158/0008-5472.CAN-09-0462
17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells
Ying Wang1, Xiuquan Ma3, Shousheng Yan1, Shensi Shen1, Huiling Zhu1, Yuan Gu1, Hongbing Wang2, Guowei Qin2 and Qiang Yu1
Departments of 1 Pharmacology and 2 Natural Products Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; and 3 Department of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, People's Republic of China
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs frequently in cancer cells and contributes to oncogenesis. Among the members of STAT family, STAT3 plays a pivotal role in the development and progression of human tumors. The STAT3-mediated signaling pathway has been recognized as a promising anticancer target. Here, we show that 17-Hydroxy-jolkinolide B (HJB), a diterpenoid from the Chinese medicinal herb Euphorbia fischeriana Steud, strongly inhibits interleukin (IL)-6–induced as well as constitutive STAT3 activation. Furthermore, we show that HJB directly targets the JAK family kinases, JAK1, JAK2, and TYK2, by inducing dimerization of the JAKs via cross-linking. Addition of DTT or glutathione prevents the JAK cross-linking and blocks the inhibitory effects of HJB on IL-6–induced STAT3 activation, suggesting that HJB may react with cystein residues of JAKs to form covalent bonds that inactivate JAKs. Liquid chromatography/mass spectrometry analysis confirmed that each HJB reacted with two thiols. The effect of HJB on the JAK/STAT3 pathway is specific as HJB has no effect on platelet-derived growth factor, epidermal growth factor, or insulin-like growth factor I signaling pathways. Finally, we show that HJB inhibits growth and induces apoptosis of tumor cells, particularly those tumor cells with constitutively activated STAT3. We propose that the natural compound HJB is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor.
