Research Papers:
A novel small molecule STAT3 inhibitor, LY5, inhibits cell viability, colony formation, and migration of colon and liver cancer cells
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Abstract
Chongqiang Zhao1,2,*, Wenlong Wang1,3,*, Wenying Yu4, David Jou5, Yina Wang1, Haiyan Ma1, Hui Xiao5, Hua Qin6, Cuntai Zhang7, Jiagao Lü1, Sheng Li1, Chenglong Li8, Jiayuh Lin5, Li Lin1
1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
2Division of Cardiology, Tianjin First Center Hospital, Tianjin, P.R. China
3Division of Pediatric Intensive Care Unit, Pediatric Cardiac Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
4Division of State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P.R. China
5Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
6Division of Gastroenterology, Departments of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
7Departments of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
8Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA
*These authors have contributed equally to this work
Correspondence to:
Li Lin, e-mail: [email protected]
Keywords: LY5, STAT3, colon cancer, liver cancer
Received: July 02, 2015 Accepted: January 27, 2016 Published: February 11, 2016
ABSTRACT
Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated in human liver and colon cancer cells and is required for cancer cell viability, survival and migration. Therefore, inhibition of STAT3 signaling may be a viable therapeutic approach for these two cancers. We recently designed a non-peptide small molecule STAT3 inhibitor, LY5, using in silico site-directed Fragment-based drug design (FBDD). The inhibitory effect on STAT3 phosphorylation, cell viability, migration and colony forming ability by LY5 were examined in human liver and colon cancer cells. We demonstrated that LY5 inhibited constitutive Interleukin-6 (IL-6)-induced STAT3 phosphorylation, STAT3 nuclear translocation, decreased STAT3 downstream targeted gene expression and induced apoptosis in liver and colon cancer cells. LY5 had little effect on STAT1 phosphorylation mediated by IFN-γ. Inhibition of persistent STAT3 phosphorylation by LY5 also inhibited colony formation, cell migration, and decreased the viability of liver cancer and colon cancer cells. Furthermore, LY5 inhibited STAT3 phosphorylation and suppressed colon tumor growth in a mouse model in vivo. Our results suggest that LY5 is a potent STAT3 inhibitor and may be a potential drug candidate for liver and colon cancer therapy.
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