Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer. Endocr Relat Cancer 2015 Jun;22(3):319-29
Date
05/15/2015Pubmed ID
25972243DOI
10.1530/ERC-14-0510Scopus ID
2-s2.0-84937029829 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.
Author List
Mehta A, Zhang L, Boufraqech M, Zhang Y, Patel D, Shen M, Kebebew EMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Drug Screening Assays, Antitumor
High-Throughput Screening Assays
Humans
Mice
Mice, Inbred NOD
Oligopeptides
Thyroid Carcinoma, Anaplastic
Thyroid Neoplasms
Transfection
