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Previous studies have confirmed that emodin has inhibitory effects on various solid tumors, such as osteosarcoma, liver cancer, prostate cancer and glioma. This study aimed to investigate the effects and mechanisms of emodin-induced necroptosis in the glioma cell line U251 by targeting the TNF-\u03b1\/RIP1\/RIP3 signaling pathway. We found that emodin could significantly inhibit U251 cell proliferation, and the viability of U251 cells treated with emodin was reduced in a dose- and time-dependent manner. Flow cytometry assays and Hoechst-PI staining assays showed that emodin induced apoptosis and necroptosis. Real-time PCR and western blot analysis showed that emodin upregulated the levels of TNF-\u03b1, RIP1, RIP3 and MLKL. Furthermore, the RIP1 inhibitor Nec-1 and the RIP3 inhibitor GSK872 attenuated the killing effect of emodin on U251 cells. In addition, emodin could increase the levels of TNF-\u03b1, RIP1, RIP3 and MLKL in vivo. The results demonstrate that emodin could induce necroptosis in glioma possibly through the activation of the TNF-\u03b1\/RIP1\/RIP3 axis. These studies provide novel insight into the induction of necroptosis by emodin and indicate that emodin might be a potential candidate for treating glioma through the necroptosis pathway.<\/jats:p>","DOI":"10.1007\/s10637-019-00764-w","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T06:02:31Z","timestamp":1553752951000},"page":"50-59","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Emodin induced necroptosis in the glioma cell line U251 via the TNF-\u03b1\/RIP1\/RIP3 pathway"],"prefix":"10.1007","volume":"38","author":[{"given":"Jiabin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangkui","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6558-9405","authenticated-orcid":false,"given":"Feng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,28]]},"reference":[{"key":"764_CR1","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1016\/S0140-6736(11)61346-9","volume":"379","author":"K Behin A; Hoangxuan","year":"2012","unstructured":"Behin A; Hoangxuan K, Carpentier AF, Delattre JY (2012) Primary brain tumours in adults. 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The author Genhua Li declares that he has no conflict of interest. The author Guangkui Han declares that he has no conflict of interest. The author Song Feng declares that he has no conflict of interest. The author Yuhan Liu declares that he has no conflict of interest. The author Jun Chen declares that he has no conflict of interest. The author Chen Liu declares that he has no conflict of interest. The author Feng Jin declares that he has no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Animal experiments were approved by the Laboratory Animal Research Committee of Huazhong University of Science and Technology (SYXK2016\u20130057, 1 June 2018), and all study procedures followed internationally accepted principles and the Guidelines of the Care and Use.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}