Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells

paymanz

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http://www.cancerletters.info/article/S ... 6/abstract

Highlights

•Cyproheptadine inhibits proliferation and induces apoptosis in urothelial carcinoma cells in vitro and in vivo.
•Cyproheptadine suppresses mTOR through the GSK3β/TSC2/mTOR and GSK3β/β-catenin axes.
•Cells treated with cyproheptadine result in reduction of c-Myc, induction of p21, p27 and stabilization of Rb.
•RNA-Seq found that the effect of cyproheptadine on UC cells may be due to up-regulation of ANGPTL4.

Abstract

Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.
 
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