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

Rushworth, Linda K. and Hewit, Kay and Munnings-Tomes, Sophie and Somani, Sukrut and James, Daniel and Shanks, Emma and Dufès, Christine and Straube, Anne and Patel, Rachana and Leung, Hing Y. (2019) Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment. British Journal of Cancer. pp. 1-11. ISSN 1532-1827

[img]
Preview
Text (Rushworth-etal-BJC2019-Repurposing-screen-identifies-mebendazole-as-a-clinical-candidate-to-synergise)
Rushworth_etal_BJC2019_Repurposing_screen_identifies_mebendazole_as_a_clinical_candidate_to_synergise.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo

Download (2MB)| Preview

    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 chemo-resistant prostate cancer by enhancing the efficacy of docetaxel. Methods: We performed a drug repurposing screen 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 kill 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 dynamic, leading to increased apoptosis and reduced tumour growth. Our data supports a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.