Dovitinib在肝癌中诱导细胞凋亡并且克服了索拉的耐药性
本帖最后由 tshwangq 于 2012-3-16 00:19 编辑内容我翻译不好，直接贴过来吧
转自:mct.aacrjournals.org/content/11/2/452.short
Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1–Mediated Inhibition of STAT3
Wei-Tien Tai3,4, Ann-Lii Cheng2,3, Chung-Wai Shiau5, Chun-Yu Liu5,6, Ching-Huai Ko7, Mai-Wei Lin7, Pei-Jer Chen1, and Kuen-Feng Chen1,3
+ Author Affiliations
Authors' Affiliations: Departments of 1Medical Research and 2Oncology, 3National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital; 4Graduate Institute of Molecular Medicine, National Taiwan University College of Medicine; 5Institute of Biopharmaceutical Sciences, National Yang-Ming University; 6Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei; and 7Cell Engineering Lab, Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu, Taiwan
Corresponding Author:
Kuen-Feng Chen, Department of Medical Research, National Taiwan University Hospital, No 7, Chung-Shan S Rd, Taipei 100, Taiwan. Phone: 886-2-23123456, ext. 63548; Fax: 886-2-23225329; E-mail: kfchen1970@ntu.edu.tw
Abstract
The multiple kinase inhibitor dovitinib is currently under clinical investigation for hepatocellular carcinoma (HCC). Here, we investigated the mechanistic basis for the effects of dovitinib in HCCs. Dovitinib showed significant antitumor activity in HCC cell lines PLC5, Hep3B, Sk-Hep1, and Huh-7. Dovitinib downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 and subsequently reduced the levels of expression of STAT3-related proteins Mcl-1, survivin, and cyclin D1 in a time-dependent manner. Ectopic expression of STAT3 abolished the apoptotic effect of dovitinib, indicating that STAT3 is indispensable in mediating the effect of dovitinib in HCC. SHP-1 inhibitor reversed downregulation of p-STAT3 and apoptosis induced by dovitinib, and silencing of SHP-1 by RNA interference abolished the effects of dovitinib on p-STAT3, indicating that SHP-1, a protein tyrosine phosphatase, mediates the effects of dovitinib. Notably, dovitinib increased SHP-1 activity in HCC cells. Incubation of dovitinib with pure SHP-1 protein enhanced its phosphatase activity, indicating that dovitinib upregulates the activity of SHP-1 via direct interactions. In addition, dovitinib induced apoptosis in two sorafenib-resistant cell lines through inhibition of STAT3, and sorafenib-resistant cells showed significant activation of STAT3, suggesting that targeting STAT3 may be a useful approach to overcome drug resistance in HCC. Finally, in vivo, dovitinib significantly suppressed growth of both Huh-7 and PLC5 xenograft tumors and downregulated p-STAT3 by increasing SHP-1 activity. In conclusion, dovitinib induces significant apoptosis in HCC cells and sorafenib-resistant cells via SHP-1–mediated inhibition of STAT3. Mol Cancer Ther; 11(2); 452–63. ©2011 AACR.
Received June 14, 2011.
Revision received November 27, 2011.
Accepted December 7, 2011. 完全不懂...谁好心点来拯救下我这个高考英语不过80，看英语就像鸟语的人吧，:'(:'(:'(
还好那年英语难的出奇:L:L 我这英文也是半吊子
我看似乎是说可以逆转多吉美？那就牛逼大了。 还有一个问题，这种要怎么搞到？ 贴心小袄 发表于 2012-3-17 17:50 static/image/common/back.gif
完全不懂...谁好心点来拯救下我这个高考英语不过80，看英语就像鸟语的人吧，
还好那年英语难的出 ...
你英语居然这么高啊？我高考150满分的英语，只考了32 这个dovitinib应该已经出来了，中文名字：多韦替尼，北京307医院在招募入组，听他们说全国共有4个地方在招入组，其他3个地方不知道在哪。
吃了6周的这个药，CT对比检查本人肝包膜外面的2个转移灶略有缩小，肝肾隐窝处（肝S6段，手术区）的几个小结节略有增大，自己怀疑肝肾隐窝处的稍有增大而包膜外能缩小可能跟两个地方的供血有关系。
我也想了解这个多韦替尼是个啥东西，有点担心这个要控制不住肿瘤的发展，想增加 阿西替尼或者依维莫司试试
找时间也写一下自己的治疗贴，便于与病友交流。 longjin 发表于 2012-9-16 20:04 static/image/common/back.gif
这个dovitinib应该已经出来了，中文名字：多韦替尼，北京307医院在招募入组，听他们说全国共有4个地方在招入 ...
上海中山有招募的 按这样的道理，岂不是打干扰素也能起到同样的效果？ 请问这药有最近试用情况吗？
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