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Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer
Wang M.3; Shim J.S.1; Li R.-J.1; Dang Y.1; He Q.1; Das M.1; Liu J.O.1
2014-10-01
Source PublicationBritish Journal of Pharmacology
ISSN14765381 00071188
Volume171Issue:19Pages:4478-4489
Abstract

Background and Purpose 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. Experimental Approach 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. Key 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 G cell cycle arrest in prostate cancer cells. Clofoctol also inhibited prostate cancer xenograft growth in vivo without apparent toxicity. Conclusion and Implications 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.

DOI10.1111/bph.12800
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000342668400011
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Cited Times [WOS]:15   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Johns Hopkins University
2.Fudan University Shanghai Medical College
3.Soochow University
4.Ministry of Education China
5.Universidade de Macau
Recommended Citation
GB/T 7714
Wang M.,Shim J.S.,Li R.-J.,et al. Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer[J]. British Journal of Pharmacology,2014,171(19):4478-4489.
APA Wang M..,Shim J.S..,Li R.-J..,Dang Y..,He Q..,...&Liu J.O..(2014).Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer.British Journal of Pharmacology,171(19),4478-4489.
MLA Wang M.,et al."Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer".British Journal of Pharmacology 171.19(2014):4478-4489.
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