Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy

Chia-Hsien Wu, Li-Yuan Bai, Ming-Hsui Tsai, Po-Chen Chu, Chang-Fang Chiu, Michael Yuanchien Chen, Shih-Jiuan Chiu, Jo-Hua Chiang, Jing-Ru Weng

研究成果: 雜誌貢獻文章

18 引文 (Scopus)

摘要

Phenothiazines (PTZs) have been used for the antipsychotic drugs for centuries. However, some of these PTZs have been reported to exhibit antitumor effects by targeting various signaling pathways in vitro and in vivo. 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)-10H-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 in vivo as it, administrated at 10 and 20 mg/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.
原文英語
頁(從 - 到)27540
期刊Scientific Reports
6
DOIs
出版狀態已發佈 - 六月 9 2016

指紋

Drug Repositioning
Phenothiazines
Antineoplastic Agents
Antipsychotic Agents
Trifluoperazine
Mouth Neoplasms
Autophagy
Pharmacology
Adenosine Monophosphate
Growth
Heterografts
Protein Kinases
Reactive Oxygen Species
Neoplasms
Biomarkers
Phosphorylation
Apoptosis
phenothiazine
Therapeutics

引用此文

Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy. / Wu, Chia-Hsien; Bai, Li-Yuan; Tsai, Ming-Hsui; Chu, Po-Chen; Chiu, Chang-Fang; Chen, Michael Yuanchien; Chiu, Shih-Jiuan; Chiang, Jo-Hua; Weng, Jing-Ru.

於: Scientific Reports, 卷 6, 09.06.2016, p. 27540.

研究成果: 雜誌貢獻文章

Wu, Chia-Hsien ; Bai, Li-Yuan ; Tsai, Ming-Hsui ; Chu, Po-Chen ; Chiu, Chang-Fang ; Chen, Michael Yuanchien ; Chiu, Shih-Jiuan ; Chiang, Jo-Hua ; Weng, Jing-Ru. / Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy. 於: Scientific Reports. 2016 ; 卷 6. 頁 27540.
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abstract = "Phenothiazines (PTZs) have been used for the antipsychotic drugs for centuries. However, some of these PTZs have been reported to exhibit antitumor effects by targeting various signaling pathways in vitro and in vivo. 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)-10H-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 in vivo as it, administrated at 10 and 20 mg/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.",
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