Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer
AuthorsBibby, Becky A
Pereira, Ronnie R
McArt, D. G.
Bristow, Robert G
Williams, K. J.
West, Catharine M L
AffiliationTranslational Radiobiology Group, Division of Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX
MetadataShow full item record
AbstractBackground: The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. Methods: Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. Results: Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. Conclusion: Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.
CitationBibby BAS, Thiruthaneeswaran N, Yang L, Pereira RR, More E, McArt DG, et al. Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer. BMC Urol. 2021 Jul 1;21(1).
- Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53.
- Authors: Supiot S, Hill RP, Bristow RG
- Issue date: 2008 Apr
- Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions.
- Authors: Potiron VA, Abderrahmani R, Giang E, Chiavassa S, Di Tomaso E, Maira SM, Paris F, Supiot S
- Issue date: 2013 Jan
- DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions.
- Authors: Stewart GD, Nanda J, Katz E, Bowman KJ, Christie JG, Brown DJ, McLaren DB, Riddick AC, Ross JA, Jones GD, Habib FK
- Issue date: 2011 Jan 15
- Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules.
- Authors: Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, Graner M, Frederick B, Agarwal R, Deep G
- Issue date: 2015 Jul
- Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition.
- Authors: Jonsson M, Ragnum HB, Julin CH, Yeramian A, Clancy T, Frikstad KM, Seierstad T, Stokke T, Matias-Guiu X, Ree AH, Flatmark K, Lyng H
- Issue date: 2016 Oct 11