High-throughput drug library screening identifies colchicine as a thyroid cancer inhibitor
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Le Zhang1,2, Zhaoying Yang1,2, Letizia Granieri3, Adrian Pasculescu3, Alessandro Datti3,4, Sylvia L. Asa2,5, Zheli Xu1,2, Shereen Ezzat2,6
1Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, P.R. China
2Ontario Cancer Institute and The Endocrine Oncology Site Group, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada
3SMART Laboratory for High-Throughput Screening Programs, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON, Canada
4Department of Agricultural, Food, and Environmental Sciences, University of Perugia, Perugia, Italy
5Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada
6Department of Medicine, University of Toronto, Toronto, ON, Canada
Shereen Ezzat, e-mail: [email protected]
Zheli Xu, e-mail: [email protected]
Keywords: thyroid cancer, colchicine, BRAF, BRAF resistance, high throughput drug screening
Received: November 20, 2015 Accepted: February 09, 2016 Published: March 03, 2016
We employed a high-throughput drug library screening platform to identify novel agents affecting thyroid cancer cells. We used human thyroid cancer cell lines to screen a collection of approximately 5200 small molecules with biological and/or pharmacologial properties. Parallel primary screens yielded a number of hits differentially active between thyroid and melanoma cells. Amongst compounds specifically targeting thyroid cancer cells, colchicine emerged as an effective candidate. Colchicine inhibited cell growth which correlated with G2 cell cycle arrest and apoptosis. These effects were hampered through inhibition of MEK1/2 and JNK. In contrast, inhibition of p38-MAPK had little effect, and AKT had no impact on colchicine action. Systemic colchicine inhibited thyroid cancer progression in xenografted mice. These findings demonstrate that our screening platform is an effective vehicle for drug reposition and show that colchicine warrants further attention in well-defined clinical niches such as thyroid cancer.
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