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However, some of these PTZs have been reported to exhibit antitumor effects by targeting various signaling pathways <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Thus, this study was aimed at exploiting trifluoperazine, one of PTZs, to develop potent antitumor agents. This effort culminated in A4 [10-(3-(piperazin-1-yl)propyl)-2-(trifluoromethyl)-10<jats:italic>H<\/jats:italic>-phenothiazine] which exhibited multi-fold higher apoptosis-inducing activity than the parent compound in oral cancer cells. Compared to trifluoperazine, A4 demonstrated similar regulation on the phosphorylation or expression of multiple molecular targets including Akt, p38 and ERK. In addition, A4 induced autophagy, as evidenced by increased expression of the autophagy biomarkers LC3B-II and Atg5 and autophagosomes formation. The antitumor activity of A4 also related to production of reactive oxygen species and adenosine monophosphate-activated protein kinase. Importantly, the antitumor utility of A4 was extended <jats:italic>in vivo<\/jats:italic> as it, administrated at 10 and 20\u2009mg\/kg intraperitoneally, suppressed the growth of Ca922 xenograft tumors. In conclusion, the ability of A4 to target diverse aspects of cancer cell growth suggests its value in oral cancer therapy.<\/jats:p>","DOI":"10.1038\/srep27540","type":"journal-article","created":{"date-parts":[[2016,6,9]],"date-time":"2016-06-09T09:37:59Z","timestamp":1465465079000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents\u2013A drug repurposing strategy"],"prefix":"10.1038","volume":"6","author":[{"given":"Chia-Hsien","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yuan","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Hsui","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Chen","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Fang","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Yuanchien","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Jiuan","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo-Hua","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Ru","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,9]]},"reference":[{"key":"BFsrep27540_CR1","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1016\/S0140-6736(08)60728-X","volume":"371","author":"A Argiris","year":"2008","unstructured":"Argiris, A., Karamouzis, M. 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