{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:35:38Z","timestamp":1775540138960,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,7]],"date-time":"2024-01-07T00:00:00Z","timestamp":1704585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1H1A2010153"],"award-info":[{"award-number":["2022R1H1A2010153"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Drug repurposing is a strategy for discovering new applications of existing drugs for use in various diseases. Despite the use of structured networks in drug research, it is still unclear how drugs interact with one another or with genes. Prostate adenocarcinoma is the second leading cause of cancer mortality in the United States, with an estimated incidence of 288,300 new cases and 34,700 deaths in 2023. In our study, we used integrative information from genes, pathways, and drugs for machine learning methods such as clustering, feature selection, and enrichment pathway analysis. We investigated how drugs affect drugs and how drugs affect genes in human pancreatic cancer cell lines that were derived from bone metastases of grade IV prostate cancer. Finally, we identified significant drug interactions within or between clusters, such as estradiol-rosiglitazone, estradiol-diclofenac, troglitazone-rosiglitazone, celecoxib-rofecoxib, celecoxib-diclofenac, and sodium phenylbutyrate-valproic acid.<\/jats:p>","DOI":"10.3390\/ijms25020765","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:59:20Z","timestamp":1704700760000},"page":"765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inferring Drug Set and Identifying the Mechanism of Drugs for PC3"],"prefix":"10.3390","volume":"25","author":[{"given":"Shinuk","family":"Kim","sequence":"first","affiliation":[{"name":"College of Engineering, Sangmyung University, Cheonan 31066, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"811044","DOI":"10.3389\/fpubh.2022.811044","article-title":"Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019","volume":"10","author":"Wang","year":"2022","journal-title":"Front Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kim, S. (2022). Systemic Efficacy of Sirolimus via the ERBB Signaling Pathway in Breast Cancer. Processes, 10.","DOI":"10.3390\/pr10030552"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ma, Y., Hu, J., Zhang, N., Dong, X., Li, Y., Yang, B., Tian, W., and Wang, X. (2016). Prediction of Candidate Drugs for Treating Pancreatic Cancer by Using a Combined Approach. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149896"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Badkas, A., De Landtsheer, S., and Sauter, T. (2021). Topological network measures for drug repositioning. Brief. Bioinform., 22.","DOI":"10.1093\/bib\/bbaa357"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrd.2018.168","article-title":"Drug repurposing: Progress, challenges and recommendations","volume":"18","author":"Pushpakom","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.procs.2018.10.411","article-title":"Analysis of computational gene prioritization approaches","volume":"143","author":"Raj","year":"2018","journal-title":"Procedia Comput. Sci."},{"key":"ref_7","first-page":"115","article-title":"The LNCaP cell line\u2013A new model for studies on human prostatic carcinoma","volume":"37","author":"Horoszewicz","year":"1980","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0377-0427(87)90125-7","article-title":"Silhouettes: A graphical aid to the interpretation and validation of cluster analysis","volume":"20","author":"Rousseeuw","year":"1987","journal-title":"J. Comput. Appl. Math."},{"key":"ref_9","first-page":"100","article-title":"Algorithm AS 136: A k-means clustering algorithm","volume":"28","author":"Hartigan","year":"1979","journal-title":"J. R. Stat. Soc. Ser. C (Appl. Stat.)"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kim, S., Kang, M., Lee, S., Bae, S., Han, S., Jang, J.Y., and Park, T. (2014). Identifying molecular subtypes related to clinicopathologic factors in pancreatic cancer. Biomed. Eng. Online, 13.","DOI":"10.1186\/1475-925X-13-S2-S5"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bishop, C.M. (1995). Neural Networks for Pattern Recognition, Oxford University Press.","DOI":"10.1093\/oso\/9780198538493.001.0001"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ins.2019.05.072","article-title":"Feature selection using neighborhood entropy-based uncertainty measures for gene expression data classification","volume":"502","author":"Sun","year":"2019","journal-title":"Inf. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"833","DOI":"10.2165\/00003495-200161060-00019","article-title":"Rofecoxib: A review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis","volume":"61","author":"Matheson","year":"2001","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1185\/030079907X219526","article-title":"The VIOXX in Prostate Cancer Prevention study: Cardiovascular events observed in the rofecoxib 25 mg and placebo treatment groups","volume":"23","author":"Gann","year":"2007","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.eururo.2004.08.024","article-title":"Combination therapy with rofecoxib and finasteride in the treatment of men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH)","volume":"47","author":"Bosman","year":"2005","journal-title":"Eur. Urol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1158\/1078-0432.CCR-04-1877","article-title":"Celecoxib inhibits prostate cancer growth: Evidence of a cyclooxygenase-2-independent mechanism","volume":"11","author":"Patel","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1136\/bmj.332.7553.1302","article-title":"Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials","volume":"332","author":"Kearney","year":"2006","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1002\/art.21887","article-title":"Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: High-risk subgroups and time course of risk","volume":"54","author":"Solomon","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.urology.2015.04.044","article-title":"Diclofenac suppository as a preemptive analgesia in ultrasound-guided biopsy of prostate: Randomized controlled trial","volume":"86","author":"Haroon","year":"2015","journal-title":"Urology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Montgomery, B., Nelson, P.S., Vessella, R., Kalhorn, T., Hess, D., and Corey, E. (2010). Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-244"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"36869","DOI":"10.1074\/jbc.R100029200","article-title":"The multifaceted mechanisms of estradiol and estrogen receptor signaling","volume":"276","author":"Hall","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1152\/physrev.00010.2007","article-title":"Estradiol and the developing brain","volume":"88","author":"McCarthy","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0301-0082(00)00025-3","article-title":"Neuroprotection by estradiol","volume":"63","author":"Azcoitia","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map. Using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Lamb","year":"2006","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/44565","article-title":"Learning the parts of objects by non-negative matrix factorization","volume":"401","author":"Lee","year":"1999","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"374","DOI":"10.2144\/03342mt01","article-title":"TM4: A free, open-source system for microarray data management and analysis","volume":"34","author":"Saeed","year":"2003","journal-title":"Biotechniques"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2307\/1217208","article-title":"The comparison of dendrograms by objective methods","volume":"11","author":"Sokal","year":"1962","journal-title":"Taxonomy"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3251","DOI":"10.1093\/bioinformatics\/btm369","article-title":"GSEA-P: A desktop application for Gene Set Enrichment Analysis","volume":"23","author":"Subramanian","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1073\/pnas.091062498","article-title":"Significance analysis of microarrays applied to the ionizing radiation response","volume":"98","author":"Tusher","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","unstructured":"(2024, January 04). Giorgio. Feature Selection Library. MATLAB Central File Exchange. Available online: https:\/\/www.mathworks.com\/matlabcentral\/fileexchange\/56937-feature-selection-library."},{"key":"ref_32","unstructured":"Bradley, P.S., and Mangasarian, O.L. (1998, January 24\u201327). Feature Selection via Concave Minimization and Support Vector Machines. Proceedings of the Fifteenth International Conference on Machine Learning, Madison, WI, USA."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D380","DOI":"10.1093\/nar\/gkv1277","article-title":"STITCH 5: Augmenting protein-chemical interaction networks with tissue and affinity data","volume":"44","author":"Szklarczyk","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D1091","DOI":"10.1093\/nar\/gkt1068","article-title":"DrugBank 4.0: Shedding new light on drug metabolism","volume":"42","author":"Law","year":"2014","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/765\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:41:39Z","timestamp":1760103699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/2\/765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,7]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25020765"],"URL":"https:\/\/doi.org\/10.3390\/ijms25020765","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,7]]}}}