Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy.
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.
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Chia-Hsien
CH
Wu
College of Medicine, China Medical University, Taichung 404, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Li-Yuan
LY
Bai
Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
Ming-Hsui
MH
Tsai
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Po-Chen
PC
Chu
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.|Cancer Center, China Medical University Hospital, Taichung 404, Taiwan.
Chang-Fang
CF
Chiu
Department of Oral &Maxillofacial Surgery, China Medical University Hospital, Taichung 404, Taiwan.|School of Dentistry, China Medical University, Taichung 404, Taiwan.
Michael Yuanchien
MY
Chen
School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
Shih-Jiuan
SJ
Chiu
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
Jo-Hua
JH
Chiang
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
Jing-Ru
JR
Weng
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004249:DNA Damage; D058492:Drug Repositioning; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy*; D010640:Phenothiazines / Q000494:pharmacology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D014408:Biomarkers, Tumor; D010640:Phenothiazines; D017382:Reactive Oxygen Species