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Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment
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Rushworth, Linda, Hewit, Kay, Munnings-Tomes, Sophie, Somani, Sukrut, James, Daniel, Shanks, Emma, Dufès, Christine, Straube, Anne, Patel, Rachana and Leung, Hing (2020) Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment. British Journal of Cancer, 122 . pp. 517-527. doi:10.1038/s41416-019-0681-5 ISSN 0007-0920.
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WRAP-repurposing-screen-identifies-mebendazole-candidate-prostate-Straube-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2342Kb) | Preview |
Official URL: https://doi.org/10.1038/s41416-019-0681-5
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.
| Item Type: | Journal Article | ||||||||||||||||||||||||
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| Subjects: | Q Science > Q Science (General) R Medicine > R Medicine (General) |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Prostate, Prostate -- Cancer , Prostate -- Cancer -- Treatment, Prostate -- Cancer -- Chemotherapy, Antiandrogens -- Therapeutic use | ||||||||||||||||||||||||
| Journal or Publication Title: | British Journal of Cancer | ||||||||||||||||||||||||
| Publisher: | Nature Publishing Group | ||||||||||||||||||||||||
| ISSN: | 0007-0920 | ||||||||||||||||||||||||
| Official Date: | 18 February 2020 | ||||||||||||||||||||||||
| Dates: |
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| Volume: | 122 | ||||||||||||||||||||||||
| Page Range: | pp. 517-527 | ||||||||||||||||||||||||
| DOI: | 10.1038/s41416-019-0681-5 | ||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
| Copyright Holders: | The Authors | ||||||||||||||||||||||||
| Date of first compliant deposit: | 8 January 2020 | ||||||||||||||||||||||||
| Date of first compliant Open Access: | 15 January 2020 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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