title: Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer.
abstract: OBJECTIVE
  Finding new indications for existing drugs, also known as drug repositioning or repurposing, is a powerful approach to accelerate drug discovery and development. The unfolded protein response pathways have been proposed to be a viable target for developing new anticancer drugs.
  
  
  METHODS
  We screened the Johns Hopkins Drug Library for inhibitors of prostate cancer cell proliferation to identify new antiprostate cancer treatments among known drugs. We systematically investigated the mechanism underlying the anticancer activity of a hit and assessed its efficacy in blocking prostate tumour growth in a mouse model.
  
  
  RESULTS
  The antibacterial drug clofoctol was identified as a novel inhibitor of prostate cancer cell proliferation. Morphologically, cells treated with clofoctol were found to undergo massive vacuolization, reminiscent of endoplasmic reticulum stress. Indeed, all three unfolded protein response pathways including inositol requiring enzyme 1, double-stranded RNA-activated PK-like ER kinase and activating transcription factor 6 were found to be activated by clofoctol. Activation of unfolded protein response pathways by clofoctol led to the inhibition of protein translation in cells and the induction of G1 cell cycle arrest in prostate cancer cells. Clofoctol also inhibited prostate cancer xenograft growth in vivo without apparent toxicity.
  
  
  CONCLUSIONS
  Our findings revealed clofoctol as a novel activator of the unfolded protein response pathways and a promising inhibitor of prostate cancer. As clofoctol has been used in the clinic for years, it is ready for clinical evaluation as a novel antiprostate cancer drug candidate.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College, Soochow University, Suzhou, China; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Wang
authors.forename: Joong Sup
authors.initials: JS
authors.lastname: Shim
authors.forename: Ruo-Jing
authors.initials: RJ
authors.lastname: Li
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.forename: Qingli
authors.initials: Q
authors.lastname: He
authors.forename: Manisha
authors.initials: M
authors.lastname: Das
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002722:Chlorobenzenes; D003408:Cresols / Q000494:pharmacology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002722:Chlorobenzenes; D003408:Cresols; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C018874:clofoctol