Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment.

Rushworth, L. K., Hewit, K., Munnings-Tomes, S., Somani, S., James, D., Shanks, E., Dufès, C., Straube, A., Patel, R. and Leung, H. Y. (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) (PMID:31844184) (PMCID:PMC7028732)

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: Articles
• Additional Information: Funding information This work was supported by the Prostate Cancer Foundation Challenge Award (R.P. and H.Y.L.), Cancer Research UK Beatson Institute (C596/ A17196 and CRUK A15151; H.Y.L.), Lister Institute of Preventive Medicine and Wellcome Trust Investigator Award (200870/Z/16/Z; A.S.), Worldwide Cancer Research (16-1303; C.D. and H.Y.L.) and The Dunhill Medical Trust (R463/0216; C.D. and S.S.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leung, Professor Hing and Shanks, Dr Emma and James, Mr Daniel and Patel, Dr Rachana and Hewit, Dr Kay
• Authors: Rushworth, L. K., Hewit, K., Munnings-Tomes, S., Somani, S., James, D., Shanks, E., Dufès, C., Straube, A., Patel, R., and Leung, H. Y.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: British Journal of Cancer
• Publisher: Springer Nature
• ISSN: 0007-0920
• ISSN (Online): 1532-1827
• Published Online: 17 December 2019
• Copyright Holders: Copyright © The Author(s) 2019
• First Published: First published in British Journal of Cancer 122:517–527
• Publisher Policy: Reproduced under a Creative Commons licence