Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F.
Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F.
复制标题
DOI：
10.1038/labinvest.2015.46
复制
发表时间：
2015-06
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
Despite significant progress in diagnostics and therapeutics, over fifty thousand patients die from colorectal cancer annually. Hence there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase(LDH) release and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F dependent genes, E2F1-Rb binding and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically we demonstrate that at low concentrations, triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Triptolide and Minnelide are effective against colon cancer in multiple pre-clinical models.
登录
查看更多内容
影响因子：
29.4
作者：
Mujumdar N;Mackenzie TN;Dudeja V;Chugh R;Antonoff MB;Borja-Cacho D;Sangwan V;Dawra R;Vickers SM;Saluja AK
通讯作者：
Saluja AK
DOI：
10.1016/j.jss.2010.03.067
发表时间：
2010-10
期刊：
The Journal of surgical research
影响因子：
--
作者：
Clawson KA;Borja-Cacho D;Antonoff MB;Saluja AK;Vickers SM
通讯作者：
Vickers SM
影响因子：
37.3
作者：
Chen Z;Sangwan V;Banerjee S;Mackenzie T;Dudeja V;Li X;Wang H;Vickers SM;Saluja AK
通讯作者：
Saluja AK
影响因子：
3.6
作者：
Zhu, Wenbo;Ou, Yanqiu;Yan, Guangmei
通讯作者：
Yan, Guangmei
影响因子：
4.8
作者：
Banerjee, Sulagna;Sangwan, Veena;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.