TY - JOUR
T1 - Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy
AU - Wu, Chia-Hsien
AU - Bai, Li-Yuan
AU - Tsai, Ming-Hsui
AU - Chu, Po-Chen
AU - Chiu, Chang-Fang
AU - Chen, Michael Yuanchien
AU - Chiu, Shih-Jiuan
AU - Chiang, Jo-Hua
AU - Weng, Jing-Ru
PY - 2016/6/9
Y1 - 2016/6/9
N2 - 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.
AB - 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.
KW - Journal Article
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-84974555439&origin=resultslist&sort=plf-f&src=s&st1=Pharmacological+exploitation+of+the+phenothiazine+antipsychotics+to+develop+novel+antitumor+agents-A+drug+repurposing+strategy&st2=&sid=cd98a04ce0257ed31894772604b8f803&sot=b&sdt=b&sl=141&s=TITLE-ABS-KEY%28Pharmacological+exploitation+of+the+phenothiazine+antipsychotics+to+develop+novel+antitumor+agents-A+drug+repurposing+strategy%29&relpos=0&citeCnt=6&searchTerm=
UR - https://www.scopus.com/results/citedbyresults.uri?sort=plf-f&cite=2-s2.0-84974555439&src=s&imp=t&sid=9ab70aec9d31aa28a292e5f609f1c817&sot=cite&sdt=a&sl=0&origin=recordpage&editSaveSearch=&txGid=bb8273429ded1ac5b10e417619f77f27
U2 - 10.1038/srep27540
DO - 10.1038/srep27540
M3 - Article
C2 - 27277973
SN - 2045-2322
VL - 6
SP - 27540
JO - Scientific Reports
JF - Scientific Reports
ER -