Format

Send to

Choose Destination
Cancer Lett. 2016 Jan 1;370(1):56-65. doi: 10.1016/j.canlet.2015.09.018. Epub 2015 Oct 21.

Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways.

Author information

1
Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan.
2
Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, 539 Jhongsiao Road, Chiayi 600, Taiwan.
3
Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.
4
Department of Internal Medicine, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Da-Lin, Chiayi, Taiwan.
5
Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan.
6
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of General Surgery, Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
7
Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi, Taiwan; Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, 539 Jhongsiao Road, Chiayi 600, Taiwan. Electronic address: cdh199712@gmail.com.
8
Graduate Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chiayi, Taiwan; Department of Life Science, National Chung Cheng University, 168 University Road, Min-Hsiung, Chiayi, Taiwan. Electronic address: biowyc@ccu.edu.tw.

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.

KEYWORDS:

ANGPTL4; Cyproheptadine; Urothelial carcinoma; Wnt/β-catenin signaling; mTOR signaling

PMID:
26454215
DOI:
10.1016/j.canlet.2015.09.018
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center