title: Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma.
abstract: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC.
  
  
  
  A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R.
  
  
  
  Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell-cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo
  
  
  
  Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC. Clin Cancer Res; 22(14); 3458-66. ©2016 AACR.
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland. Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kei
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: SUNY Upstate Medical University at Syracuse, Syracuse, New York.
authors.forename: Raju
authors.initials: R
authors.lastname: Chelluri
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Myriem
authors.initials: M
authors.lastname: Boufraqech
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Naris
authors.initials: N
authors.lastname: Nilubol
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland. kebebewe@mail.nih.gov.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D051176:beta Catenin; D009534:Niclosamide; D020169:Caspases