title: A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities.
abstract: OBJECTIVE
  Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells.
  
  
  METHODS
  Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity.
  
  
  RESULTS
  We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo.
  
  
  CONCLUSIONS
  Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.
authors: Departments of Obstetrics and Gynecology, and Physical Examination, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors: Youlin
authors: Y
authors: Deng
authors: Zhongliang
authors: Z
authors: Wang
authors: Fugui
authors: F
authors: Zhang
authors: Min
authors: M
authors: Qiao
authors: Zhengjian
authors: Z
authors: Yan
authors: Qiang
authors: Q
authors: Wei
authors: Jing
authors: J
authors: Wang
authors: Hao
authors: H
authors: Liu
authors: Jiaming
authors: J
authors: Fan
authors: Yulong
authors: Y
authors: Zou
authors: Junyi
authors: J
authors: Liao
authors: Xue
authors: X
authors: Hu
authors: Liqun
authors: L
authors: Chen
authors: Xinyi
authors: X
authors: Yu
authors: Rex C
authors: RC
authors: Haydon
authors: Hue H
authors: HH
authors: Luu
authors: Hongbo
authors: H
authors: Qi
authors: Tong-Chuan
authors: TC
authors: He
authors: Junhui
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000977:Antiparasitic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058492:Drug Repositioning; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C494112:ELK1 protein, human; C079439:MXD1 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D050807:ets-Domain Protein Elk-1; D007334:Insulin-Like Growth Factor I; D009534:Niclosamide; D017526:Receptor, IGF Type 1