Www.research.manchester.ac.uk



Repurposing FDA Approved Drugs as Radiosensitizers for Treating Hypoxic Prostate CancerBecky AS. Bibby*1, Niluja Thiruthaneeswaran*1,2, Lingjian Yang1, Ronnie R. Pereira1,3, Elisabet More1, Darragh G. McArt4, Paul O’Reilly4, Robert G. Bristow1,3,6, Kaye J. Williams5, Ananya Choudhury1,6 and Catharine M.L West1,61 Division of Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK2 Sydney Medical School, University of Sydney, Australia 3 Translational Oncogenomics, CRUK Manchester Institute and CRUK Manchester Centre, Manchester, UK4 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK5 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK 6 Christie Hospital NHS Foundation Trust, Manchester, UK* Joint first author 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. BACKGROUNDThe goal of drug repurposing is to find new clinical indications for existing pharmaceuticals that are currently on the market or failed in phase II/III trials. Repurposing is feasible because disease mechanisms are multifactorial and small drug molecules have multiple targets. Drug repurposing is both time and cost effective since the pharmacology and toxicity profile of approved drugs are already established. Approximately 30% of food and drug authority (FDA) applications for repurposed drugs are approved compared with 10% for new drugs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmF1bDwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (6). Any positive hit from this algorithm has already been identified as a safe therapeutic and can be progressed into a Phase I/II radiotherapy combination trial. Computation-based approaches to drug repurposing provide an opportunity to identify novel agents to combine with radiotherapy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFybWE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (14-16). The retrospective analysis of hypoxia gene signature biomarkers within clinical trials confirmed patients with hypoxic tumors benefit most from hypoxia modification PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub3VzdHJ1cDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

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ADDIN EN.CITE.DATA (14, 17). Hypoxia gene signature biomarkers have been derived for multiple cancers and do not necessarily recapitulate across disease sites hence disease site-specific signatures have been developed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJyaXM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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Pn==

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Pn==

ADDIN EN.CITE.DATA (18). Recently, we derived a gene signature for assessing hypoxia in prostate cancer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (19). The aim of this study was to investigate whether the transcription network associated with our hypoxia gene signature could be used in QUADrATIC to identify FDA approved drugs for potential repurposing for the treatment of hypoxic prostate cancer. METHODSIdentifying Hypoxia Associated GenesGenes significantly differentially expressed after 24 h exposure to 1% oxygen in more than two cell lines (DU145, PC3, LNCaP, PNT2) were identified previously as seed genes. For each cell line, genes differentially expressed between normoxia and hypoxia conditions across triplicates were selected using a rank product probability of false positive rate <0.05 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (19). The 848 seed genes were used to build gene co-expression networks using the publicly available GSE21032 or TCGA cohorts PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXlsb3I8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (22). The user inputs their genes of interest, in this case the 103 GSE21032 and 66 TCGA hypoxia-associated genes, and the STRING database assembles a network of protein-protein interactions based on experimental evidence and predicted function. The associations in STRING include direct physical interactions and predicted indirect functional interactions. The protein-protein interactions are presented as networks, in which nodes represent proteins and the lines associations between proteins. The protein-protein association strength takes the form of a p-value that evaluates multiple channels of evidence as well as the chance of a random interaction between the protein pair ADDIN EN.CITE <EndNote><Cite><Author>von Mering</Author><Year>2005</Year><RecNum>23</RecNum><DisplayText>(23)</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983803">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>von Mering, C.</author><author>Jensen, L. J.</author><author>Snel, B.</author><author>Hooper, S. D.</author><author>Krupp, M.</author><author>Foglierini, M.</author><author>Jouffre, N.</author><author>Huynen, M. A.</author><author>Bork, P.</author></authors></contributors><auth-address>European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. mering@embl-heidelberg.de</auth-address><titles><title>STRING: known and predicted protein-protein associations, integrated and transferred across organisms</title><secondary-title>Nucleic Acids Res</secondary-title><alt-title>Nucleic acids research</alt-title></titles><periodical><full-title>Nucleic Acids Res</full-title><abbr-1>Nucleic acids research</abbr-1></periodical><alt-periodical><full-title>Nucleic Acids Res</full-title><abbr-1>Nucleic acids research</abbr-1></alt-periodical><pages>D433-7</pages><volume>33</volume><number>Database issue</number><edition>2004/12/21</edition><keywords><keyword>*Databases, Protein</keyword><keyword>Multiprotein Complexes/physiology</keyword><keyword>Protein Interaction Mapping</keyword><keyword>Proteins/chemistry/*physiology</keyword><keyword>Sequence Homology, Amino Acid</keyword><keyword>Systems Integration</keyword></keywords><dates><year>2005</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>0305-1048</isbn><accession-num>15608232</accession-num><urls></urls><custom2>PMC539959</custom2><electronic-resource-num>10.1093/nar/gki005</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(23).Connectivity Mapping QUADrATiC uses the LINCS database to identify connections between gene expression profiles and FDA-approved drugs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PJmFwb3M7UmVpbGx5PC9BdXRob3I+PFllYXI+MjAxNjwv

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ADDIN EN.CITE.DATA (24). In other words, up-regulated genes associated with a poor prognosis (hazard ratio [HR] >1) comprise the up-regulated set of the signature while up-regulated genes associated with a good prognosis (HR < 1) form the down-regulated set. Cell LinesThree prostate cancer cell lines were used to test drugs in vitro: DU145 (HTB-81), PC3 (CRL-1435) and LNCaP (CRL-1740). The cell lines were obtained from the American Type Culture Collection and authenticated by short tandem repeat profiling using the Promega Powerplex 21 system. Cell lines were cultured under normal conditions (37?C, 5% CO2 in air), screened for mycoplasma and authenticated using short tandem repeat profiling. DU145 and LNCaP cells were cultured in RPMI 1640 (Sigma-Aldrich, UK) with 10% fetal bovine serum (FBS) and 2 mM L-glutamine (Sigma-Aldrich, UK). PC3 cells were cultured in Ham's F12 (Gibco, ThermoFisher, UK) with 10% FBS and 2 mM L-glutamine (Sigma-Aldrich, UK). Drug PreparationMenadione (Selleck Chem, Texas, USA), gemcitabine (Selleck Chem, Texas, USA) and tirapazamine (APExBIO, Texas, USA) were purchased in lyophilized form. Drugs were reconstituted to a concentration of 50 mM in dimethyl sulfoxide (DMSO) as recommended by the manufacturer. Stock solutions were aliquoted and stored at -80°C; aliquots were not repeatedly freeze thawed. Sulforhodamine B (SRB) Assays Cells were seeded into 96 well plates and allowed to adhere overnight in the incubator. The next day plates were treated with 0, 2, 5, 10, 50 or 100 ?M of drug or DMSO vehicle control. Following application of the drug, cells were immediately moved into a 0.1% O2 hypoxia chamber (Don Whitley Scientific, Bingley, UK) or kept in a normoxia incubator for 24 h. The assay endpoint was either 24 h or 4 days post-treatment. For the 24 h time point, the cells were fixed and stained after 24 h incubation with the drug. For the 4-day time point, the drug was removed after 24 h and fresh media added to the cells. Plates were incubated for a further 4 days in normoxia. Cells were fixed and then stained with sulforhodamine B according to the published method ADDIN EN.CITE <EndNote><Cite><Author>Vichai</Author><Year>2006</Year><RecNum>25</RecNum><IDText>Sulforhodamine B colorimetric assay for cytotoxicity screening</IDText><DisplayText>(25)</DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983803">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vichai, V.</author><author>Kirtikara, K.</author></authors></contributors><auth-address>National Center for Genetic Engineering and Biotechnology (BIOTEC), 113 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Patumtani 12120, Thailand. vanicha@biotec.or.th</auth-address><titles><title>Sulforhodamine B colorimetric assay for cytotoxicity screening</title><secondary-title>Nat Protoc</secondary-title><alt-title>Nature protocols</alt-title></titles><periodical><full-title>Nat Protoc</full-title><abbr-1>Nature protocols</abbr-1></periodical><alt-periodical><full-title>Nat Protoc</full-title><abbr-1>Nature protocols</abbr-1></alt-periodical><pages>1112-6</pages><volume>1</volume><number>3</number><edition>2007/04/05</edition><keywords><keyword>Cell Count/*methods</keyword><keyword>Cell Culture Techniques/methods</keyword><keyword>Colorimetry/*methods</keyword><keyword>Fluorescent Dyes</keyword><keyword>Rhodamines/*metabolism</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Toxicity Tests/*methods</keyword></keywords><dates><year>2006</year></dates><isbn>1750-2799</isbn><accession-num>17406391</accession-num><urls></urls><electronic-resource-num>10.1038/nprot.2006.179</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(25).Clonogenic AssaysCells were seeded into plug seal T25 flasks and allowed to adhere overnight in the incubator, with plug seal caps kept loose. The next day media were removed and replaced with fresh media containing the drug (10 ?M menadione or 8 nM gemcitabine) or DMSO (vehicle control). Untreated control flasks had fresh media applied. Cells exposed to normoxia, with or without the drug, were incubated with plug seal caps left loose in the incubator for 24 h. Cells exposed to 0.1% oxygen for 24 h, with or without the drug, were incubated with plug seal caps left loose in the H35 hypoxystation (Don Whitley Scientific, Bingley, UK). After 24 h plug seal caps were tightened on the flasks in the hypoxystation to maintain hypoxic conditions during irradiation. Cells were irradiated with x-rays delivered at 0.95 Gy/min using a Faxitron X-ray machine (Tucson, Arizona, USA). After irradiation cells were immediately harvested, counted and seeded onto 6-well plates ADDIN EN.CITE <EndNote><Cite><Author>Franken</Author><Year>2006</Year><RecNum>26</RecNum><DisplayText>(26)</DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983804">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Franken, N. A.</author><author>Rodermond, H. M.</author><author>Stap, J.</author><author>Haveman, J.</author><author>van Bree, C.</author></authors></contributors><auth-address>Laboratory for Experimental Oncology and Radiobiology, Department of Radiotherapy, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands. n.a.franken@amc.uva.nl</auth-address><titles><title>Clonogenic assay of cells in vitro</title><secondary-title>Nat Protoc</secondary-title><alt-title>Nature protocols</alt-title></titles><periodical><full-title>Nat Protoc</full-title><abbr-1>Nature protocols</abbr-1></periodical><alt-periodical><full-title>Nat Protoc</full-title><abbr-1>Nature protocols</abbr-1></alt-periodical><pages>2315-9</pages><volume>1</volume><number>5</number><edition>2007/04/05</edition><keywords><keyword>Cell Culture Techniques</keyword><keyword>Cell Proliferation/drug effects/*radiation effects</keyword><keyword>Colony-Forming Units Assay/*methods</keyword><keyword>Humans</keyword><keyword>Radiation Dosage</keyword></keywords><dates><year>2006</year></dates><isbn>1750-2799</isbn><accession-num>17406473</accession-num><urls></urls><electronic-resource-num>10.1038/nprot.2006.339</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(26). Plates were incubated for 7-21 days until colonies had formed, fixed and stained using crystal violet solution (70% methanol (v/v), 0.1% crystal violet). Plates were imaged on a GelCount machine (Oxford Optronix, Abingdon, UK) and colonies counted using an optimized CHARM algorithm in the GelCount software. The surviving fraction was calculated for each biological repeat (experiments ran on separate days with cells of a different passage) using the mean number of colonies across the six individual wells. The concentration of DMSO was 0.02% (v/v) for menadione and 0.000016% (v/v) for gemcitabine. Sensitizer enhancement ratio (SER) was calculated as the ratio between the doses needed for 1 log kill with or without the drug. Statistical AnalysisData are presented as mean ± standard error of the mean (SEM). GraphPad PRISM 8 was used to plot graphs, radiation survival curves were fitted with the linear quadratic model. Surviving fractions at 2 Gy (SF2) and SER values were extrapolated from the fit of the linear quadratic model using PRISM 8. GraphPad PRISM 8 was used to perform the F-test and statistical analysis, p values <0.05 were considered significant. RESULTSHypoxia Associated Genes Co-expression networks in the GSE21032 and TCGA cohorts identified hypoxia-associated genes (Supplementary Tables 1 and 2). Proteins encoded by the genes in the two networks interacted significantly (p<1×10-16). Figure 1 illustrates the high level of connections between the proteins in the networks. The network plots show only proteins with at least one connection. Sixty-nine of the 103 genes (67%) in the GSE21032 list had at least one connection and there was an average of 3.6 connections per node. The TCGA gene list produced a more highly connected network of protein-protein interactions with 55 of the 66 genes (83%) having at least one connection and an average of 8.2 connections. The gene lists were applied independently to the QUADrATiC connectivity mapping software to identify FDA-approved drugs.QUADrATiC Connectivity MappingDrugs with negative connections were considered able to target the phenotype of interest, in this case hypoxia in prostate cancer. Using the GSE21032 hypoxia-associated genes there were 5,348 drugs with negative z-scores, of which 2,405 were nominally significant (p<0.05). Using the TCGA hypoxia-associated genes there were 4,827 drugs with negative z-scores, of which 2,270 were nominally significant (p<0.05). The QUADrATiC interface provided summary visualizations of the top connections as bubble charts and drug and cell line connections (Supplementary Figure 1 and 2). Drug SelectionThe top 10 drugs from each of the two gene lists were ranked based on Z-score (Table 1). There were two prostate cell lines, PC3 and VCaP, in the connectivity mapping analysis but drug selection was not restricted to the highest ranking drugs identified in these cell lines (Table 2). The strength of the connection between the genes and the drug was considered more important than the cell line in which it was identified because (i) there were only two prostate cancer cell lines in the program and (ii) the importance of hypoxia across solid tumours. Two candidate drugs were selected for in vitro validation, menadione and gemcitabine, because they ranked in the top 10 in the GSE21032 and TCGA datasets in all (Table 1) and the prostate cancer (Table 2) cell lines. Menadione appeared twice in the top 10 ranked drugs in the GSE21032 and TCGA (Table 1) and was the only drug with a strong connection to the VCaP cell line in both datasets (Table 2). Gemcitabine appeared twice in the top 10 ranked drugs in the GSE21032 and once in the TCGA (Table 1) and had a strong connection to the PC3 cell line in both datasets (Table 2). Menadione and gemcitabine also had negative Z-scores in the PC3 and VCaP cell lines (Supplementary Table 5). The approved application, mechanism of action and reported peak plasma concentrations for menadione and gemcitabine are summarized in Table 3. Hypoxia Selective CytotoxicityMenadione and gemcitabine were tested alongside the known bioreductively activated tirapazamine. In the DU145, PC3 and LNCaP cell lines tirapazamine demonstrated hypoxia selective cytotoxicity 24 h (Supplementary Figure 3) and 4 days (Figure 2) following drug exposure). There was no loss in cytotoxicity for menadione and gemcitabine 4 days post-treatment in any of the three cell lines. However, hypoxic PC3 cells were more sensitive to 5 ?M menadione and 10 ?M gemcitabine than the normoxic cells after 24 h drug exposure (Supplementary Figure 3). RadiosensitizationThe radiosensitizing ability of the two FDA approved drugs was studied in DU145 and PC3 cells. The rationale for selecting DU145 in addition to PC3 for the radiosensitization experiments is because this cell line was derived from human tissue, whereas the LNCaP cell line was initially derived from human tissue but cultured in a mouse model.Vehicle control experiments confirmed DMSO did not alter surviving fraction compared to the untreated controls and DMSO plus radiation did not alter surviving fraction compared to radiation alone (Supplementary Figure 4). Figure 3 shows survival curves for the cells irradiated in normoxia and hypoxia. Oxygen enhancement ratio (OERs) calculated at the 10% survival level were 1.34 for DU145 and 1.69 for PC3 cells. Figure 4 shows menadione was a weak radiosensitizer in DU145 cells only. The SER for menadione in DU145 cells was 1.02 in normoxia and 1.15 in hypoxia. Figure 5 shows gemcitabine was also a weak radiosensitizer in DU145 cells only. The SER for gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. DISCUSSIONOur study demonstrated how a gene expression network associated with hypoxia can be used in the QUADrATIC software to identify FDA approved drugs with the potential to be repurposed. The candidate drugs selected for in vitro validation, menadione and gemcitabine, showed similar cytotoxicity in normoxia and hypoxia in three cell lines. There was also evidence that the drugs were weak radiosensitizers in normoxia and hypoxia in one of the cell lines studied. Although menadione and gemcitabine did not demonstrate hypoxia-selective cytotoxicity the drugs had similar efficacy in normoxia and hypoxia. 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ADDIN EN.CITE.DATA (31). It is uncommon for drugs studied in radiotherapy combination trials to have had their efficacy first tested under hypoxia. In future, pre-clinical testing as a justification for trial design should involve in vitro testing in hypoxia as well as normoxia.As expected, we have shown the hypoxia selective toxicity of tirapazamine. Although previously studied in PC3 cells, this is the first study of tirapazamine in DU145 and LNCaP cells. The IC50 for PC3 was 5 μM (4 days post-treatment after 24 h at 0.1% O2), which compares with literature reported IC50 doses for tirapazamine in PC3 cells of 15 ?M (4 h anoxia) and 22 ?M (48 h at 3% O2) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXR0ZXJzb248L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy

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ADDIN EN.CITE.DATA (32, 33). Tirapazamine has been shown to enhance the effect of castration induced hypoxia by inducing apoptosis and subsequently reducing tumor volume ADDIN EN.CITE <EndNote><Cite><Author>Johansson</Author><Year>2011</Year><RecNum>33</RecNum><IDText>Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model</IDText><DisplayText>(34)</DisplayText><record><rec-number>33</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983805">33</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Johansson, A.</author><author>Rudolfsson, S. H.</author><author>Kilter, S.</author><author>Bergh, A.</author></authors></contributors><titles><title>Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model</title><secondary-title>BJU Int</secondary-title></titles><periodical><full-title>BJU Int</full-title></periodical><pages>1818-24</pages><volume>107</volume><number>11</number><edition>2010/09/22</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Cell Hypoxia</keyword><keyword>Disease Models, Animal</keyword><keyword>Hypoxia</keyword><keyword>Immunohistochemistry</keyword><keyword>Male</keyword><keyword>Orchiectomy</keyword><keyword>Organ Culture Techniques</keyword><keyword>Oxygen Consumption</keyword><keyword>Prostatic Neoplasms</keyword><keyword>Random Allocation</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword><keyword>Statistics, Nonparametric</keyword><keyword>Tirapazamine</keyword><keyword>Triazines</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1464-410X</isbn><accession-num>20860653</accession-num><urls><related-urls><url>;(34). Furthermore, hypoxia induces adaptive androgen independence and confers resistance to androgen deprivation therapy (ADT) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (35). Tirapazamine in combination with ADT has the potential to eliminate hypoxic tumor cells and prevent the development of ADT resistant clones. However, a Phase III trial that randomised head and neck cancer patients to chemoradiotherapy alone or with tirapazamine showed no benefit PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaXNjaGluPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

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ADDIN EN.CITE.DATA (37). The physiological level of oxygen in the normal prostate is 3.4-3.9% but oxygen levels in prostate tumor tissue are in the range of 0.3-1.2% ADDIN EN.CITE <EndNote><Cite><Author>McKeown</Author><Year>2014</Year><RecNum>37</RecNum><IDText>Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response</IDText><DisplayText>(38)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983806">37</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKeown, S. R.</author></authors></contributors><auth-address>Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, UK.</auth-address><titles><title>Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response</title><secondary-title>Br J Radiol</secondary-title></titles><periodical><full-title>Br J Radiol</full-title></periodical><pages>20130676</pages><volume>87</volume><number>1035</number><keywords><keyword>Animals</keyword><keyword>Cell Hypoxia</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Hypoxia/*pathology</keyword><keyword>Male</keyword><keyword>Neoplasms/metabolism/*pathology/*therapy</keyword><keyword>Oxygen/metabolism</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1748-880X (Electronic)&#xD;0007-1285 (Linking)</isbn><accession-num>24588669</accession-num><urls><related-urls><url>;(38). Normoxia in this study is 21% O2 which is supraphysiological compared to the level of oxygen in the prostate gland. However, in vitro cell lines are routinely established and cultured in the laboratory under these conditions and have adapted to grow at 21% O2 and therefore the difference in gene expression may not reflect in vivo changes. The OERs for the DU145 and PC3 cell lines exposed to 0.1% O2 for 24 h were low over the dose ranges studied but similar to those previously reported for DU145 and PC3 with the exception of PC3 transfected with mir210 inhibitors giving an OER of ~2 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5RdWVybzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (39-42). Furthermore, in vitro studies have reported varying OERs depending on the duration under hypoxia with OER decreasing with time of exposure under hypoxia for the same cell lines ADDIN EN.CITE <EndNote><Cite><Author>Z?lzer</Author><Year>2002</Year><RecNum>40</RecNum><DisplayText>(41)</DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983806">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Z?lzer, F.</author><author>Streffer, C.</author></authors></contributors><titles><title>Increased radiosensitivity with chronic hypoxia in four human tumor cell lines</title><secondary-title>Int J Radiat Oncol Biol Phys</secondary-title></titles><periodical><full-title>Int J Radiat Oncol Biol Phys</full-title><abbr-1>International journal of radiation oncology, biology, physics</abbr-1></periodical><pages>910-20</pages><volume>54</volume><number>3</number><keywords><keyword>Carcinoma, Squamous Cell</keyword><keyword>Cell Cycle</keyword><keyword>Cell Hypoxia</keyword><keyword>Cell Survival</keyword><keyword>Dose-Response Relationship, Radiation</keyword><keyword>Genes, p53</keyword><keyword>Humans</keyword><keyword>Melanoma</keyword><keyword>Oxygen</keyword><keyword>Radiation Tolerance</keyword><keyword>S Phase</keyword><keyword>Time Factors</keyword><keyword>Tumor Cells, Cultured</keyword><keyword>Tumor Stem Cell Assay</keyword></keywords><dates><year>2002</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0360-3016</isbn><accession-num>12377345</accession-num><urls><related-urls><url>(02)02963-2</electronic-resource-num><language>eng</language></record></Cite></EndNote>(41). The guidelines for preclinical and early phase assessment of radiosensitizers state that relatively low SER values in the range 1.2-1.5 may indicate a useful effect, particularly if sensitization occurs at clinically relevant doses of radiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJyaW5ndG9uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

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ADDIN EN.CITE.DATA (45). This normoxic radiosensitization with gemcitabine is comparable to the radiosensitizing effects of other chemotherapeutic agents such as 5-FU ADDIN EN.CITE <EndNote><Cite><Author>Valdes</Author><Year>2013</Year><RecNum>45</RecNum><IDText>Re-evaluation of cellular radiosensitization by 5-fluorouracil: high-dose, pulsed administration is effective and preferable to conventional low-dose, chronic administration</IDText><DisplayText>(46)</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983807">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Valdes, G.</author><author>Iwamoto, K. S.</author></authors></contributors><titles><title>Re-evaluation of cellular radiosensitization by 5-fluorouracil: high-dose, pulsed administration is effective and preferable to conventional low-dose, chronic administration</title><secondary-title>Int J Radiat Biol</secondary-title></titles><periodical><full-title>Int J Radiat Biol</full-title></periodical><pages>851-62</pages><volume>89</volume><number>10</number><edition>2013/05/15</edition><keywords><keyword>Antineoplastic Agents</keyword><keyword>Cell Line, Tumor</keyword><keyword>Dose Fractionation, Radiation</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Drug Administration Schedule</keyword><keyword>Fluorouracil</keyword><keyword>Humans</keyword><keyword>Radiation Tolerance</keyword><keyword>Radiation-Sensitizing Agents</keyword></keywords><dates><year>2013</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1362-3095</isbn><accession-num>23607451</accession-num><urls><related-urls><url>;(46).Menadione, also known as vitamin K3, is a quinone and synthetic vitamin that can be converted into active vitamin K2 in the body. Menadione induces the production of reactive oxygen species (ROS) through redox cycling and disrupts the interaction between HIF-1a and its coactivator p300 thus inhibiting HIF-1a transcriptional activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZXJhc2ltZW5rbzwvQXV0aG9yPjxZZWFyPjIwMDI8L1ll

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ADDIN EN.CITE.DATA (50, 51). PSA velocity and PSA doubling time decreased in 15 of 17 patients suggesting value in progressing apatone into the Phase III setting.Gemcitabine is a chemotherapeutic agent used to treat several cancers, it is a nucleoside analogue that is incorporated into the DNA and inhibits DNA synthesis resulting in cell death. Nucleoside analogues such as gemcitabine are considered as potential radiosensitizers because they inhibit the repair of radiation induced DNA damage ADDIN EN.CITE <EndNote><Cite><Author>Ruiz van Haperen</Author><Year>1993</Year><RecNum>51</RecNum><DisplayText>(52)</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983808">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ruiz van Haperen, V. W.</author><author>Veerman, G.</author><author>Vermorken, J. B.</author><author>Peters, G. J.</author></authors></contributors><auth-address>Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.</auth-address><titles><title>2&apos;,2&apos;-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines</title><secondary-title>Biochem Pharmacol</secondary-title><alt-title>Biochemical pharmacology</alt-title></titles><periodical><full-title>Biochem Pharmacol</full-title></periodical><pages>762-6</pages><volume>46</volume><number>4</number><edition>1993/08/17</edition><keywords><keyword>Animals</keyword><keyword>Antimetabolites, Antineoplastic/*pharmacology</keyword><keyword>DNA, Neoplasm/biosynthesis/*drug effects</keyword><keyword>Deoxycytidine/*analogs &amp; derivatives/pharmacology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>RNA, Neoplasm/biosynthesis/*drug effects</keyword><keyword>Tumor Cells, Cultured</keyword></keywords><dates><year>1993</year><pub-dates><date>Aug 17</date></pub-dates></dates><isbn>0006-2952 (Print)&#xD;0006-2952</isbn><accession-num>8363650</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(52). In muscle invasive bladder cancer evidence from phase I/II trials supports the concurrent administration of gemcitabine and radiotherapy as a bladder preservation strategy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA (55). The radiosensitizing effects of gemcitabine in breast cancer are greater than the effects reported in this study for prostate cancer. However, the radiosensitizing effect of gemcitabine is greater under normoxia agrees with our findings. A limitation of our study is that radiosensitizing effects were weak and only observed in DU145 cells. This cell line is derived from a central nervous system metastasis of primary prostate adenocarcinoma ADDIN EN.CITE <EndNote><Cite><Author>Stone</Author><Year>1978</Year><RecNum>55</RecNum><IDText>Isolation of a human prostate carcinoma cell line (DU 145)</IDText><DisplayText>(56)</DisplayText><record><rec-number>55</rec-number><foreign-keys><key app="EN" db-id="fs9e0pwdewdstqeevt1p5t52z0z0trarpfw2" timestamp="1601983809">55</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stone, K. R.</author><author>Mickey, D. D.</author><author>Wunderli, H.</author><author>Mickey, G. H.</author><author>Paulson, D. F.</author></authors></contributors><titles><title>Isolation of a human prostate carcinoma cell line (DU 145)</title><secondary-title>Int J Cancer</secondary-title></titles><periodical><full-title>Int J Cancer</full-title></periodical><pages>274-81</pages><volume>21</volume><number>3</number><keywords><keyword>Acid Phosphatase</keyword><keyword>Adenocarcinoma</keyword><keyword>Aged</keyword><keyword>Aneuploidy</keyword><keyword>Brain</keyword><keyword>Brain Neoplasms</keyword><keyword>Cell Line</keyword><keyword>Chromosome Aberrations</keyword><keyword>Culture Techniques</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Neoplasm Metastasis</keyword><keyword>Prostatic Neoplasms</keyword></keywords><dates><year>1978</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0020-7136</isbn><accession-num>631930</accession-num><urls><related-urls><url>;(56). In comparison, the PC3 cell line is characteristic of neuroendocrine-like prostate cancer, which represents less than 2% of cases and is biologically distinct from the more common adenocarcinoma subtype PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (59). A second limitation is that effects were only studied in cell lines grown as monolayers, an in vitro spheroid model may incorporate physiological hypoxia into the model. Although it is worth noting that, the in vitro data utilized by the QUADrATIC connectivity mapping software was obtained from monolayer cultured under 21% O2.Two approaches have been employed to identify FDA-approved drug for repurposing: in silico analytics and experimental screening studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (2). In a high-throughput oxygen consumption screen, atovaquone was shown to reduce oxygen consumption PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2h0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (60). Atovaquone is an FDA approved anti-malarial with a similar chemical structure to menadione. Atovaquone was shown to reduce tumor hypoxia and increase radiosensitivity at pharmacological concentrations in spheroids in vitro and in vivo PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bc2h0b248L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (60). Atovaquone is currently being tested in phase I clinical trial for its ability to alleviate tumor hypoxia in lung cancer (NCT02628080). CONCLUSIONIn summary, this study highlights how connectivity mapping can be used to identify FDA approved drugs linked to biological phenotypes for potential repurposing. Our work shows the importance of downstream validation and proof-of-principle studies when identifying drugs for repurposing using in silico analytical approaches. Tirapazamine is an effective hypoxia-selective agent in prostate cancer cell lines and could be tested alongside ADT in future studies. In the DU145 cell line, menadione was a hypoxic radiosentiziter and gemcitabine was a normoxic radiosensitizer. Gemcitabine could be further investigated given that the guidelines for preclinical and early phase assessment of radiosensitizers report an SER in the range of 1.2-1.5 could be clinically useful. DeclarationsEthics approval and consent to participateNot applicableConsent for publicationNot applicableAvailability of data and materialsAll data analysed during this study are included in this published article and itssupplementary information files. Generated data from each experimental repeat are available from the corresponding author on reasonable peting interestsThe authors declare no competing interests.AcknowledgmentsNot applicableFunding This study was funded by the Cancer Research UK Manchester Centre (C147/A18083 and C147/A25254), Prostate Cancer UK (PG14-008-TR2) and the Movember Foundation as part of the Belfast-Manchester Centre of Excellence (CEO13-2-004). Professor Catharine West and Professor Ananya Choudhury are supported by the NIHR Manchester Biomedical Research Centre. The funding bodies were not involved in the concept, design, data analysis or preparation of manuscript. Author contributionsAll authors have read and approved the final manuscript. BB, CW and LJ conceptualization. BB and NT study design and experimental plan. BB, NT, EM conducted the experiments. LY and RP contributed to bioinformatics and data analysis. DM and PO design of QUADrATIC software. BB, NT and CW wrote the manuscript. BB did the figures preparation. CW, AC, RGB, KW review of experimental design, final edits and approval of manuscript.AbbreviationsCMapconnectivity map projectLINCSlibrary of integrated cellular signaturesQUADrATiCQueens University Belfast Accelerated Drug and Transcriptomic ConnectivityTCGAThe Cancer Genome AtlasOERoxygen enhancement ratioSERsensitizer enhancement ratioReferences ADDIN EN.REFLIST 1.Graul AI, Sorbera L, Pina P, Tell M, Cruces E, Rosa E, et al. The Year's New Drugs & Biologics - 2009. Drug news & perspectives. 2010;23(1):7-36.2.Cha Y, Erez T, Reynolds IJ, Kumar D, Ross J, Koytiger G, et al. Drug repurposing from the perspective of pharmaceutical companies. British journal of pharmacology. 2018;175(2):168-80.3.Ahmad SS, Crittenden MR, Tran PT, Kluetz PG, Blumenthal GM, Bulbeck H, et al. Clinical Development of Novel Drug-Radiotherapy Combinations. Clin Cancer Res. 2019;25(5):1455-61.4.Lamb J. The Connectivity Map: a new tool for biomedical research. Nat Rev Cancer. 2007;7(1):54-60.5.O'Reilly PG, Wen Q, Bankhead P, Dunne PD, McArt DG, McPherson S, et al. QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics. BMC Bioinformatics. 2016;17(1):198.6.Wen Q, Dunne PD, O'Reilly PG, Li G, Bjourson AJ, McArt DG, et al. KRAS mutant colorectal cancer gene signatures identified angiotensin II receptor blockers as potential therapies. Oncotarget. 2017;8(2):3206-25.7.Sharma RA, Plummer R, Stock JK, Greenhalgh TA, Ataman O, Kelly S, et al. Clinical development of new drug-radiotherapy combinations. Nature reviews Clinical oncology. 2016;13(10):627-42.8.Society AC. Cancer Facts & Figures. Atlanta; 2018.9.King A BJ. Cancer registration statistics, England: 2016. 2018.10.Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019;10(2):63-89.11.Milosevic M, Warde P, Menard C, Chung P, Toi A, Ishkanian A, et al. Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res. 2012;18(7):2108-14.12.Lawton CA, Coleman CN, Buzydlowski JW, Forman JD, Marcial VA, DelRowe JD, et al. Results of a phase II trial of external beam radiation with etanidazole (SR 2508) for the treatment of locally advanced prostate cancer (RTOG Protocol 90-20). International journal of radiation oncology, biology, physics. 1996;36(3):673-80.13.Thiruthaneeswaran N YK, Valentine J, Patel U, Choudhury A, Hoskin P, Alonzi R. Prostate Radiotherapy in Conjunction with Carbogen and Nicotinamide. A phase Ib/II Study. (PROCON). ASTRO conference2017.14.Toustrup K, S?rensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J, et al. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol. 2012;102(1):122-9.15.Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(15):1777-83.16.Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(33):4912-8.17.Yang L, Taylor J, Eustace A, Irlam JJ, Denley H, Hoskin PJ, et al. A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients. Clin Cancer Res. 2017;23(16):4761-8.18.Harris BH, Barberis A, West CM, Buffa FM. Gene Expression Signatures as Biomarkers of Tumour Hypoxia. Clin Oncol (R Coll Radiol). 2015;27(10):547-60.19.Yang L, Roberts D, Takhar M, Erho N, Bibby BAS, Thiruthaneeswaran N, et al. Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer. EBioMedicine. 2018;31:182-9.20.Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11-22.21.Vincent DB, Jean-Loup G, Renaud L, Etienne L. Fast unfolding of communities in large networks. Journal of Statistical Mechanics: Theory and Experiment. 2008;2008(10):P10008.22.Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic acids research. 2017;45(D1):D362-d8.23.von Mering C, Jensen LJ, Snel B, Hooper SD, Krupp M, Foglierini M, et al. STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic acids research. 2005;33(Database issue):D433-7.24.Zhang SD, Gant TW. A simple and robust method for connecting small-molecule drugs using gene-expression signatures. BMC Bioinformatics. 2008;9:258.25.Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nature protocols. 2006;1(3):1112-6.26.Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nature protocols. 2006;1(5):2315-9.27.Strese S, Fryknas M, Larsson R, Gullbo J. Effects of hypoxia on human cancer cell line chemosensitivity. BMC cancer. 2013;13:331.28.Warren HR, Hejmadi M. Effect of hypoxia on chemosensitivity to 5-fluorouracil in SH-SY5Y neuroblastoma cells. Bioscience Horizons: The International Journal of Student Research. 2016;9.29.Yoshiba S, Ito D, Nagumo T, Shirota T, Hatori M, Shintani S. Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G(1) phase cell cycle arrest. Oral Oncol. 2009;45(2):109-15.30.Fujita H, Hirose K, Sato M, Fujioka I, Fujita T, Aoki M, et al. Metformin attenuates hypoxia-induced resistance to cisplatin in the HepG2 cell line. Oncol Lett. 2019;17(2):2431-40.31.Forde JC, Perry AS, Brennan K, Martin LM, Lawler MP, Lynch TH, et al. Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells. Urol Oncol. 2012;30(6):912-9.32.Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, et al. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res. 2007;13(13):3922-32.33.Jiang F, Yang B, Fan L, He Q, Hu Y. Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives. Bioorg Med Chem Lett. 2006;16(16):4209-13.34.Johansson A, Rudolfsson SH, Kilter S, Bergh A. Targeting castration-induced tumour hypoxia enhances the acute effects of castration therapy in a rat prostate cancer model. BJU Int. 2011;107(11):1818-24.35.Geng H, Xue C, Mendonca J, Sun XX, Liu Q, Reardon PN, et al. Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy. Nature communications. 2018;9(1):4972.36.Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(18):2989-95.37.Hammond EM, Asselin MC, Forster D, O'Connor JP, Senra JM, Williams KJ. The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin Oncol (R Coll Radiol). 2014;26(5):277-88.38.McKeown SR. Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br J Radiol. 2014;87(1035):20130676.39.Quero L, Dubois L, Lieuwes NG, Hennequin C, Lambin P. miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer. Radiother Oncol. 2011;101(1):203-8.40.Stewart GD, Nanda J, Katz E, Bowman KJ, Christie JG, Brown DJ, et al. DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions. Biochem Pharmacol. 2011;81(2):203-10.41.Z?lzer F, Streffer C. Increased radiosensitivity with chronic hypoxia in four human tumor cell lines. International journal of radiation oncology, biology, physics. 2002;54(3):910-20.42.Thompson HF, Butterworth KT, McMahon SJ, Ghita M, Hounsell AR, Prise KM. The Impact of Hypoxia on Out-of-Field Cell Survival after Exposure to Modulated Radiation Fields. Radiat Res. 2017;188(6):636-44.43.Harrington KJ, Billingham LJ, Brunner TB, Burnet NG, Chan CS, Hoskin P, et al. Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers. British journal of cancer. 2011;105(5):628-39.44.Sorensen BS, Busk M, Olthof N, Speel EJ, Horsman MR, Alsner J, et al. Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother Oncol. 2013;108(3):500-5.45.Pauwels B, Korst AE, Lardon F, Vermorken JB. Combined modality therapy of gemcitabine and radiation. The oncologist. 2005;10(1):34-51.46.Valdes G, Iwamoto KS. Re-evaluation of cellular radiosensitization by 5-fluorouracil: high-dose, pulsed administration is effective and preferable to conventional low-dose, chronic administration. Int J Radiat Biol. 2013;89(10):851-62.47.Gerasimenko JV, Gerasimenko OV, Palejwala A, Tepikin AV, Petersen OH, Watson AJ. Menadione-induced apoptosis: roles of cytosolic Ca(2+) elevations and the mitochondrial permeability transition pore. Journal of cell science. 2002;115(Pt 3):485-97.48.Loor G, Kondapalli J, Schriewer JM, Chandel NS, Vanden Hoek TL, Schumacker PT. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free radical biology & medicine. 2010;49(12):1925-36.49.Na YR, Han KC, Park H, Yang EG. Menadione and ethacrynic acid inhibit the hypoxia-inducible factor (HIF) pathway by disrupting HIF-1alpha interaction with p300. Biochemical and biophysical research communications. 2013;434(4):879-84.50.Jamison JM, Gilloteaux J, Taper HS, Summers JL. Evaluation of the in vitro and in vivo antitumor activities of vitamin C and K-3 combinations against human prostate cancer. The Journal of nutrition. 2001;131(1):158s-60s.51.Tareen B, Summers JL, Jamison JM, Neal DR, McGuire K, Gerson L, et al. A 12 week, open label, phase I/IIa study using apatone for the treatment of prostate cancer patients who have failed standard therapy. International journal of medical sciences. 2008;5(2):62-7.52.Ruiz van Haperen VW, Veerman G, Vermorken JB, Peters GJ. 2',2'-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol. 1993;46(4):762-6.53.Oh KS, Soto DE, Smith DC, Montie JE, Lee CT, Sandler HM. Combined-modality therapy with gemcitabine and radiation therapy as a bladder preservation strategy: long-term results of a phase I trial. International journal of radiation oncology, biology, physics. 2009;74(2):511-7.54.Choudhury A, Swindell R, Logue JP, Elliott PA, Livsey JE, Wise M, et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(6):733-8.55.Wouters A, Pauwels B, Burrows N, Baay M, Deschoolmeester V, Vu TN, et al. The radiosensitising effect of gemcitabine and its main metabolite dFdU under low oxygen conditions is in vitro not dependent on functional HIF-1 protein. BMC cancer. 2014;14:594.56.Stone KR, Mickey DD, Wunderli H, Mickey GH, Paulson DF. Isolation of a human prostate carcinoma cell line (DU 145). Int J Cancer. 1978;21(3):274-81.57.Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ, et al. PC3 is a cell line characteristic of prostatic small cell carcinoma. Prostate. 2011;71(15):1668-79.58.Nadal R, Schweizer M, Kryvenko ON, Epstein JI, Eisenberger MA. Small cell carcinoma of the prostate. Nat Rev Urol. 2014;11(4):213-9.59.Jonsson M, Ragnum HB, Julin CH, Yeramian A, Clancy T, Frikstad KM, et al. Hypoxia-independent gene expression signature associated with radiosensitisation of prostate cancer cell lines by histone deacetylase inhibition. British journal of cancer. 2016;115(8):929-39.60.Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, et al. The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nature communications. 2016;7:12308.Figure Legends Figure 1. Prostate cancer hypoxia-associated genes interact at the protein level. The networks, generated using the STRING database, summarize predicted associations between proteins. The nodes represent proteins and only nodes with at least one connection are shown. The edges represent protein-protein interactions and the confidence of the interaction is indicated by the thickness of the edge. (A) Sixty-nine of the 103 hypoxia-associated genes identified in GSE21032 encoded proteins that interacted with at least one other protein in the network. On average each node had 3.6 connections and there are 185 edges representing protein-protein interactions. The observed number of edges in this network was more than expected at random with a protein-protein interaction enrichment value of p<1×10-16, indicating a highly interconnected network of proteins. (B) Fifty-five of the 66 hypoxia-associated genes from the TCGA interacted with at least one other protein in the network and had an average 8.2 connections. There are 271 edges representing protein-protein interactions and number is more than expected at random (p<1×10-16), indicating a highly interconnected network of proteins. Figure 2. No hypoxia-selective cytotoxicity of menadione and gemcitabine 4 days post-treatment. DU145 (A-C), PC3 (D-F) and LNCaP (G-I) cell lines were exposed to menadione, gemcitabine or tirapazamine under normoxia or 0.1% O2 hypoxia. Only tirapazamine demonstrated hypoxia selective cytotoxicity in the cell lines. The data points represent the mean ± SEM of 2-4 values taken from each biological repeat, within each biological repeat there were 6 intra-assay replicates. Statistical analysis was performed using multiple t-tests with Holm-Sidak correction. **indicates p<0.01.Figure 3. Hypoxia increased radioresistance in the DU145 and PC3 cell lines. Cell survival curves for DU145 (A) and PC3 (B) cells, irradiated under normoxia or 0.1% O2. The data points represent the mean ± SEM of 2-4 values taken from each biological repeat. OERs were calculated at SF10% and statistical analysis was performed using the F-test.Figure 4. Menadione enhanced radiation response under hypoxic conditions in DU145 cells. (A) Menadione (10 ?M, 24 h) did not enhance the radiosensitivity of normoxic DU145 cells. (B) The SER of hypoxic DU145 cells treated with menadione was 1.15 and at 4 Gy menadione significantly reduced surviving fraction compared to radiation alone. (C) In the PC3 cell line, menadione did not enhance the radiosensitivity of normoxic or (D) hypoxic cells. The data points represent the mean ± SEM of 2-4 values taken from each biological repeat, within each biological repeat there were 6 intra-assay replicates. Statistical analysis was performed using a paired t-test (ns=not significant, * indicates p<0.05). SERs were calculated at SF10% and statistical analysis was performed using the F-test. Figure 5. Gemcitabine enhanced radiation response under normoxic and hypoxic conditions in the DU145 cells. (A) Gemcitabine (8nM, 24 h) enhanced the radiosensitivity of normoxic DU145 cells, the SER was 1.27 and at 4 Gy gemcitabine significantly reduced surviving fraction compared to radiation alone. (B) Under hypoxia the SER of gemcitabine was 1.09 and at 4 Gy gemcitabine significantly reduced surviving fraction compared to radiation alone. (C) In the PC3 cell line, gemcitabine did not enhance the radiosensitivity of normoxic or (D) hypoxic cells. The data points represent the mean ± SEM of 2-4 values taken from each biological repeat, within each biological repeat there were 6 intra-assay replicates. Statistical analysis was performed using a paired t-test (ns=not significant, * indicates p<0.05). SERs were calculated at SF10% and statistical analysis was performed using the F-test. Table 1. Top 10 FDA-approved drugs identified using connectivity mapping. GSE21032TCGARankingDrugCell LineZ-score?DrugCell LineZ-score?1MENADIONEHEPG2-15.8CLADRIBINEA375-17.52MENADIONEA375-14.0MENADIONEA375-15.63GEMCITABINEA375-13.1HOMOHARRINGTONINEPC3-15.04NICLOSAMIDEHEPG2-13.0MENADIONEHEPG2-14.65GEMCITABINEHCC515-12.1NICLOSAMIDEHEPG2-14.66CLADRIBINEA375-11.7DIGITOXINA549-14.37DIGITOXINA549-11.4AZACITIDINEA375-14.08DIGOXINPC3-11.3CLOFARABINEA375-13.99PENTAMIDINEHEPG2-11.1GEMCITABINEHCC515-13.510TENIPOSIDEA375-11.1CLADRIBINEPC3-13.3?p-values <0.001GSE21032TCGARankingDrugCell LineZ-ScoreDrugCell LineZ-Score1DIGOXINPC3-11.31HOMOHARRINGTONINEPC3-14.982OUABAINPC3-10.48CLADRIBINEPC3-13.293DIGITOXINPC3-9.83DIGITOXINPC3-13.154BISACODYLPC3-9.56MENADIONEVCAP-12.565CLOFARABINEPC3-9.42DIGOXINPC3-12.106HOMOHARRINGTONINEPC3-8.86OUABAINPC3-11.597ITRACONAZOLEPC3-8.84GEMCITABINEPC3-11.568MENADIONEVCAP-8.69AZACITIDINEPC3-10.169GEMCITABINEPC3-8.36BORTEZOMIBVCAP-10.1510TENIPOSIDEPC3-8.35CEFACLORPC3-9.92Table 2. Top 10 FDA-approved drugs identified using connectivity mapping in the prostate cancer cell lines.Table 3. Application, mechanism and peak plasma concentrations for menadione and gemcitabine.MENADIONEGEMCITABINEApproved applicationUsed in vitamin K deficiency and severe hypoprothrombinemia.Treatment of locally advanced or metastatic cancer.Mechanism of actionSynthetic vitamin K3. It is also an inhibitor of Siah2 (E3 ubiquitin ligase) ligase activity.Inhibition of DNA synthesis and inhibition of enzymes related to deoxynucleotide metabolism.Peak plasma concentration and equivalent in vitro dose115-407 ng/mL ?668.6ng-2.3?M3-6 ?g/mL11.2?M-22.4?MEquivalent in vitro dose 668.6ng-2.3?M11.2?M-22.4?M? Reported values for phytomenadione, doses up to 200mg menadione are tolerated in humans ................
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