Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer

Minghua Wang, Joong Sup Shim, Ruo Jing Li, Yongjun Dang, Qingli He, Manisha Das, Jun Liu

Research output: Contribution to journalArticle

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 G1 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.

Original languageEnglish (US)
Pages (from-to)4478-4489
Number of pages12
JournalBritish Journal of Pharmacology
Volume171
Issue number19
DOIs
StatePublished - Oct 1 2014

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Unfolded Protein Response
Prostatic Neoplasms
Anti-Bacterial Agents
Drug Repositioning
Pharmaceutical Preparations
Activating Transcription Factor 6
Cell Proliferation
G1 Phase Cell Cycle Checkpoints
Neoplasms
Endoplasmic Reticulum Stress
Double-Stranded RNA
Protein Biosynthesis
Inositol
Drug Discovery
Growth
clofoctol
Heterografts
Prostate
Phosphotransferases
Enzymes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer. / Wang, Minghua; Shim, Joong Sup; Li, Ruo Jing; Dang, Yongjun; He, Qingli; Das, Manisha; Liu, Jun.

In: British Journal of Pharmacology, Vol. 171, No. 19, 01.10.2014, p. 4478-4489.

Research output: Contribution to journalArticle

Wang, Minghua ; Shim, Joong Sup ; Li, Ruo Jing ; Dang, Yongjun ; He, Qingli ; Das, Manisha ; Liu, Jun. / Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 19. pp. 4478-4489.
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