Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment
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Published:2019-12-17
Issue:4
Volume:122
Page:517-527
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Rushworth Linda K.,Hewit Kay,Munnings-Tomes Sophie,Somani Sukrut,James Daniel,Shanks Emma,Dufès Christine,Straube Anne,Patel Rachana,Leung Hing Y.
Abstract
Abstract
Background
Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel.
Methods
We performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis.
Results
Mebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival.
Conclusions
Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.
Funder
Prostate Cancer Foundation Dunhill Medical Trust Worldwide Cancer Research Lister Institute of Preventive Medicine Cancer Research UK
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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