{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T18:09:15Z","timestamp":1770919755775,"version":"3.50.1"},"reference-count":128,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T00:00:00Z","timestamp":1563926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NCATS R21TR001731"],"award-info":[{"award-number":["NCATS R21TR001731"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 GM085273"],"award-info":[{"award-number":["P50 GM085273"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA118100"],"award-info":[{"award-number":["P30 CA118100"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1\/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.<\/jats:p>","DOI":"10.3390\/cancers11081049","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T10:48:19Z","timestamp":1563965299000},"page":"1049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Dual Actions of Ketorolac in Metastatic Ovarian Cancer"],"prefix":"10.3390","volume":"11","author":[{"given":"Laurie G.","family":"Hudson","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda S.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Epidemiology and Biostatistics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2745-550X","authenticated-orcid":false,"given":"Martha M.","family":"Grimes","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn Y.","family":"Muller","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah F.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0613-3157","authenticated-orcid":false,"given":"Angela","family":"Wandinger-Ness","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,24]]},"reference":[{"key":"ref_1","unstructured":"(2019, June 23). SEER*Explorer: An Interactive Website for SEER Cancer Statistics, Available online: https:\/\/seer.cancer.gov\/explorer\/index.html."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1002\/cncr.32004","article-title":"Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference","volume":"125","author":"Bast","year":"2019","journal-title":"Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrclinonc.2015.224","article-title":"Can advanced-stage ovarian cancer be cured?","volume":"13","author":"Narod","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nrc4019","article-title":"Rethinking ovarian cancer II: Reducing mortality from high-grade serous ovarian cancer","volume":"15","author":"Bowtell","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00280-014-2581-y","article-title":"Treatment of ovarian cancer beyond chemotherapy: Are we hitting the target?","volume":"75","author":"Garces","year":"2015","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.semcancer.2017.04.009","article-title":"Ovarian cancer stem cells more questions than answers","volume":"44","author":"Ottevanger","year":"2017","journal-title":"Semin. Cancer Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1093\/jjco\/hyv014","article-title":"Pharmacotherapy for recurrent ovarian cancer: Current status and future perspectives","volume":"45","author":"Matsumoto","year":"2015","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nwani, N.G., Sima, L.E., Nieves-Neira, W., and Matei, D. (2018). Targeting the Microenvironment in High Grade Serous Ovarian Cancer. Cancers, 10.","DOI":"10.3390\/cancers10080266"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s10585-018-9889-7","article-title":"Metastatic gynecologic malignancies: Advances in treatment and management","volume":"35","author":"Chan","year":"2018","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ctrv.2018.06.001","article-title":"Maintenance treatment of recurrent ovarian cancer: Is it ready for prime time?","volume":"69","author":"DiSilvestro","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1056\/NEJMoa1810858","article-title":"Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer","volume":"379","author":"Moore","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrc2583","article-title":"Beyond chemotherapy: Targeted therapies in ovarian cancer","volume":"9","author":"Yap","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12967-018-1389-7","article-title":"Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence","volume":"16","author":"Kim","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/PPO.0000000000000361","article-title":"Perioperative Therapies-Using Repurposed Drugs to Improve Cancer Surgery Outcomes","volume":"25","author":"Pantziarka","year":"2019","journal-title":"Cancer J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1016\/j.ejso.2017.08.010","article-title":"Perioperative therapies\u2014Enhancing the impact of cancer surgery with repurposed drugs","volume":"43","author":"Pantziarka","year":"2017","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/0008-5472.CAN-16-1536","article-title":"Surgery for Cancer: A Trigger for Metastases","volume":"77","author":"Tohme","year":"2017","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrclinonc.2014.224","article-title":"Exploiting the critical perioperative period to improve long-term cancer outcomes","volume":"12","author":"Horowitz","year":"2015","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nrclinonc.2017.194","article-title":"Perioperative events influence cancer recurrence risk after surgery","volume":"15","author":"Hiller","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S1470-2045(06)70939-1","article-title":"Mechanisms of transcoelomic metastasis in ovarian cancer","volume":"7","author":"Tan","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"C444","DOI":"10.1152\/ajpcell.00188.2015","article-title":"Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis","volume":"309","author":"Yeung","year":"2015","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1093\/annonc\/mdn386","article-title":"The effects of surgery on tumor growth: A century of investigations","volume":"19","author":"Demicheli","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_22","first-page":"69","article-title":"Long-Term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer SurgeryA Retrospective Analysis","volume":"124","author":"Wigmore","year":"2016","journal-title":"Anesthesiol. J. Am. Soc. Anesthesiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S1470-2045(12)70112-2","article-title":"Effects of regular aspirin on long-term cancer incidence and metastasis: A systematic comparison of evidence from observational studies versus randomised trials","volume":"13","author":"Algra","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.4049\/jimmunol.1501677","article-title":"Propranolol Attenuates Surgical Stress\u2014Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy","volume":"196","author":"Zhou","year":"2016","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4651","DOI":"10.1158\/1078-0432.CCR-17-0152","article-title":"Perioperative COX-2 and \u03b2-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial","volume":"23","author":"Shaashua","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e472","DOI":"10.1016\/S1470-2045(17)30536-3","article-title":"Preventive therapy for cancer","volume":"18","author":"Cuzick","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.critrevonc.2016.05.011","article-title":"The role of aspirin in colorectal cancer chemoprevention","volume":"104","year":"2016","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrclinonc.2015.105","article-title":"Inflammation and cancer: Advances and new agents","volume":"12","author":"Crusz","year":"2015","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1365-2125.2012.04290.x","article-title":"Meta-analysis on the association between non-steroidal anti-inflammatory drug use and ovarian cancer","volume":"75","author":"Ni","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/S1470-2045(18)30373-5","article-title":"Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS\/NHSII): A cohort study","volume":"19","author":"Merritt","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/S1470-2045(18)30420-0","article-title":"Does aspirin have a role in management of ovarian cancer?","volume":"19","author":"Webb","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"i17","DOI":"10.1093\/bja\/aes421","article-title":"Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis?","volume":"109","author":"Heaney","year":"2012","journal-title":"Br. J. Anaesth."},{"key":"ref_33","first-page":"2365","article-title":"Prognostic value of serum IL-8 and IL-10 in patients with ovarian cancer undergoing chemotherapy","volume":"17","author":"Zhang","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1007\/s10552-012-0063-2","article-title":"Non-steroidal anti-inflammatory drug use and ovarian cancer risk: Findings from the NIH-AARP Diet and Health Study and systematic review","volume":"23","author":"Murphy","year":"2012","journal-title":"Cancer Causes Control"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ctrv.2016.12.008","article-title":"The mortality reducing effect of aspirin in colorectal cancer patients: Interpreting the evidence","volume":"55","author":"Frouws","year":"2017","journal-title":"Cancer Treat. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Dulai, P.S., Singh, S., Marquez, E., Khera, R., Prokop, L.J., Limburg, P.J., Gupta, S., and Murad, M.H. (2016). Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: Systematic review and network meta-analysis. BMJ, 355.","DOI":"10.1136\/bmj.i6188"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ygyno.2015.12.009","article-title":"Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: A systematic review and meta-analysis of observational studies","volume":"140","author":"Verdoodt","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s10552-011-9751-6","article-title":"Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer: A systematic review","volume":"22","author":"Wilson","year":"2011","journal-title":"Cancer Causes Control"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s11912-013-0351-3","article-title":"Role of Aspirin in Cancer Prevention","volume":"15","author":"Thorat","year":"2013","journal-title":"Curr. Oncol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.canlet.2013.09.001","article-title":"Impact of non-steroidal anti-inflammatory drugs on gastrointestinal cancers: Current state-of-the science","volume":"345","author":"Sahin","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1001\/jama.2009.1112","article-title":"Aspirin Use and Survival After Diagnosis of Colorectal Cancer","volume":"302","author":"Chan","year":"2009","journal-title":"JAMA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/S0140-6736(10)61543-7","article-title":"Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials","volume":"376","author":"Rothwell","year":"2010","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/BF00541922","article-title":"Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology","volume":"26","year":"1984","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/toxsci\/kfp097","article-title":"Chiral toxicology: it\u2019s the same thing \u2026 only different","volume":"110","author":"Smith","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/bdrc.21096","article-title":"Thalidomide-induced teratogenesis: History and mechanisms","volume":"105","author":"Vargesson","year":"2015","journal-title":"Birth Defects Res. Part C Embryo Today Rew."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2165\/00003495-199600525-00006","article-title":"Chirality and nonsteroidal anti-inflammatory drugs","volume":"52","author":"Hayball","year":"1996","journal-title":"Drugs"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1002\/j.1552-4604.1994.tb01977.x","article-title":"Drug chirality: On the mechanism of R-aryl propionic acid class NSAIDs. Epimerization in humans and the clinical implications for the use of racemates","volume":"34","author":"Wechter","year":"1994","journal-title":"J. Clin. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/BF00266343","article-title":"Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs","volume":"42","author":"Evans","year":"1992","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/j.1552-4604.1996.tb05040.x","article-title":"Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs","volume":"36","author":"Carabaza","year":"1996","journal-title":"J. Clin. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"34950","DOI":"10.1074\/jbc.M110.162982","article-title":"Molecular Basis for Cyclooxygenase Inhibition by the Non-Steroidal Anti-Inflammatory Drug Naproxen","volume":"285","author":"Duggan","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"28096","DOI":"10.1074\/jbc.M701335200","article-title":"Structural Basis of Enantioselective Inhibition of Cyclooxygenase-1 by S-\u03b1-Substituted Indomethacin Ethanolamides","volume":"282","author":"Harman","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25S","DOI":"10.1002\/j.1552-4604.1998.tb04414.x","article-title":"Preclinical Enantioselective Pharmacology of (R)- and (S)-Ketorolac","volume":"38","author":"Handley","year":"1998","journal-title":"J. Clin. Pharmacol."},{"key":"ref_53","first-page":"1288","article-title":"Characterization of the Analgesic and Anti-Inflammatory Activities of Ketorolac and Its Enantiomers in the Rat","volume":"288","author":"Jett","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1002\/jps.2600780413","article-title":"Effect of R and S Enantiomers of Naproxen on Aggregation and Thromboxane Production in Human Platelets","volume":"78","author":"Kean","year":"1989","journal-title":"J. Pharm. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/0140-6736(91)92382-C","article-title":"Chirality in antirheumatic drugs","volume":"338","author":"Kean","year":"1991","journal-title":"Lancet"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1002\/j.1552-4604.1996.tb05042.x","article-title":"Chiral Kinetics and Dynamics of Ketorolac","volume":"36","author":"Mroszczak","year":"1996","journal-title":"J. Clin. Pharmacol."},{"key":"ref_57","first-page":"1487","article-title":"R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis","volume":"24","author":"Inoue","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s11060-011-0712-4","article-title":"R-flurbiprofen, a novel nonsteroidal anti-inflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells In Vitro","volume":"106","author":"Liu","year":"2012","journal-title":"J. Neuro-Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.15252\/emmm.201404168","article-title":"R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice","volume":"6","author":"Schmitz","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_60","first-page":"121","article-title":"Drug evaluation: (R)-flurbiprofen\u2014An enantiomer of flurbiprofen for the treatment of Alzheimer\u2019s disease","volume":"10","author":"Geerts","year":"2007","journal-title":"IDrugs"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1073\/pnas.0409721102","article-title":"The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis","volume":"102","author":"Kolluri","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1182\/blood-2005-02-0838","article-title":"SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma","volume":"106","author":"Yasui","year":"2005","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Oprea, T.I., Sklar, L.A., Agola, J.O., Guo, Y., Silberberg, M., Roxby, J., Vestling, A., Romero, E., Surviladze, Z., and Murray-Krezan, C. (2015). Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0142182"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1158\/1535-7163.MCT-15-0419","article-title":"R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis","volume":"14","author":"Guo","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_65","unstructured":"(2015, January 03). Roche Laboratories Toradol Oral (ketorolac tromethamine tablets). 1997\u20132013, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/019645s019lbl.pdf."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ygyno.2018.08.015","article-title":"Celecoxib versus ketorolac following robotic hysterectomy for the management of postoperative pain: An open-label randomized control trial","volume":"151","author":"Ulm","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1002\/j.1875-9114.1998.tb03113.x","article-title":"A Double-Blind Study Comparing Two Single-Dose Regimens of Ketorolac with Diclofenac in Pain Due to Cancer","volume":"18","author":"Minotti","year":"1998","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_68","first-page":"1307","article-title":"Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain","volume":"6","author":"Jameel","year":"1995","journal-title":"Int. J. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/j.1875-9114.1990.tb02577.x","article-title":"A Multiinstitutional Evaluation of the Analgesic Efficacy and Safety of Ketorolac Tromethamine, Acetaminophen plus Codeine, and Placebo in Cancer Pain","volume":"10","author":"Carlson","year":"1990","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_70","unstructured":"(2019, June 20). Ketorolac for Pain Management: A Review of the Clinical Evidence, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK254117\/."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.critrevonc.2013.01.001","article-title":"The long and winding road of non steroidal antinflammatory drugs and paracetamol in cancer pain management: A critical review","volume":"87","author":"Mercadante","year":"2013","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejogrb.2014.10.007","article-title":"Multimodal pain control is associated with reduced hospital stay following open abdominal hysterectomy","volume":"183","author":"Santoso","year":"2014","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1213\/ANE.0b013e3181d2ad07","article-title":"Do Intraoperative Analgesics Influence Breast Cancer Recurrence After Mastectomy? A Retrospective Analysis","volume":"110","author":"Forget","year":"2010","journal-title":"Anesth. Analg."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s10549-012-2094-5","article-title":"NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: Particular relevance to triple negative subgroup","volume":"134","author":"Retsky","year":"2012","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.2174\/09298673113209990250","article-title":"Reduction of Breast Cancer Relapses with Perioperative Non-Steroidal Anti-Inflammatory Drugs: New Findings and a Review","volume":"20","author":"Retsky","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1245\/s10434-013-3136-x","article-title":"Neutrophil:Lymphocyte Ratio and Intraoperative Use of Ketorolac or Diclofenac are Prognostic Factors in Different Cohorts of Patients Undergoing Breast, Lung, and Kidney Cancer Surgery","volume":"20","author":"Forget","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/jnci\/djy042","article-title":"Potential Benefit of Intra-Operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient\u2019s Body Mass Index","volume":"110","author":"Desmedt","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5064","DOI":"10.1158\/1078-0432.CCR-15-0461","article-title":"A novel pharmacologic activity of ketorolac for therapeutic benefit in ovarian cancer patients","volume":"21","author":"Guo","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1097\/EJA.0b013e32834b7d9a","article-title":"Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer?","volume":"28","author":"Forget","year":"2011","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_80","first-page":"570","article-title":"Potential Influence of the Anesthetic Technique Used during Open Radical Prostatectomy on Prostate Cancer-related OutcomeA Retrospective Study","volume":"113","author":"Wuethrich","year":"2010","journal-title":"Anesthesiol. J. Am. Soc. Anesthesiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1002\/cam4.428","article-title":"Perioperative neutrophil:lymphocyte ratio and postoperative NSAID use as predictors of survival after lung cancer surgery: A retrospective study","volume":"4","author":"Choi","year":"2015","journal-title":"Cancer Med."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Savant, S.S., Sriramkumar, S., and O\u2019Hagan, H.M. (2018). The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer. Cancers, 10.","DOI":"10.3390\/cancers10080251"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.ajog.2004.10.587","article-title":"Expression of cyclooxygenase-2 in advanced stage ovarian serous carcinoma: Correlation with tumor cell proliferation, apoptosis, angiogenesis, and survival","volume":"192","author":"Morris","year":"2005","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/1476-4598-5-62","article-title":"Ovarian epithelial cancer: A role for PGE2-synthesis and signalling in malignant transformation and progression","volume":"5","author":"Rask","year":"2006","journal-title":"Mol. Cancer"},{"key":"ref_85","first-page":"531","article-title":"Cox-2 immunohistochemical expression in epithelial ovarian carcinoma and platin sensitivity","volume":"30","author":"Menczer","year":"2009","journal-title":"Eur. J. Gynaecol. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1111\/j.1525-1438.2006.00855.x","article-title":"The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer","volume":"17","author":"Steffensen","year":"2007","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.prp.2007.11.004","article-title":"The prognostic significance of COX-2 and survivin expression in ovarian cancer","volume":"204","author":"Athanassiadou","year":"2008","journal-title":"Pathol.-Res. Pract."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13048-018-0389-9","article-title":"Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors","volume":"11","author":"Wilson","year":"2018","journal-title":"J. Ovarian Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"21353","DOI":"10.18632\/oncotarget.3860","article-title":"Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer","volume":"6","author":"Wilson","year":"2015","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.ygyno.2016.04.543","article-title":"Is aspirin use associated with a decreased risk of ovarian cancer? A systematic review and meta-analysis of observational studies with dose-response analysis","volume":"142","author":"Zhang","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.maturitas.2017.03.001","article-title":"Influence of aspirin and non-aspirin NSAID use on ovarian and endometrial cancer: Summary of epidemiologic evidence of cancer risk and prognosis","volume":"100","author":"Verdoodt","year":"2017","journal-title":"Maturitas"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ygyno.2018.06.018","article-title":"Non-aspirin NSAID use and ovarian cancer mortality","volume":"150","author":"Verdoodt","year":"2018","journal-title":"Gynecol. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/bjc.2016.39","article-title":"Analgesic medication use and risk of epithelial ovarian cancer in African American women","volume":"114","author":"Peres","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.canep.2014.12.010","article-title":"Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival","volume":"39","author":"Nagle","year":"2015","journal-title":"Cancer Epidemiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/bjc.2017.68","article-title":"Use of common analgesic medications and ovarian cancer survival: Results from a pooled analysis in the Ovarian Cancer Association Consortium","volume":"116","author":"Dixon","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1001\/jamaoncol.2018.4149","article-title":"Association of Analgesic Use with Risk of Ovarian Cancer in the Nurses\u2019 Health Studies","volume":"4","author":"Barnard","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/jnci\/djy100","article-title":"Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium","volume":"111","author":"Trabert","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"S306","DOI":"10.1016\/S0753-3322(05)80052-6","article-title":"Taxanes and COX-2 inhibitors: From molecular pathways to clinical practice","volume":"59","author":"Olsen","year":"2005","journal-title":"Biomed. Pharmacother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1093\/annonc\/mds107","article-title":"A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: The DoCaCel study","volume":"23","author":"Reyners","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1073\/pnas.1803999116","article-title":"Suppression of chemotherapy-induced cytokine\/lipid mediator surge and ovarian cancer by a dual COX-2\/sEH inhibitor","volume":"116","author":"Gartung","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ceb.2015.08.005","article-title":"Rho GTPase signalling in cell migration","volume":"36","author":"Ridley","year":"2015","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2017.09.002","article-title":"Paving the Rho in cancer metastasis: Rho GTPases and beyond","volume":"183","author":"Jansen","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/21541248.2016.1232583","article-title":"Rho GTPases: Regulation and roles in cancer cell biology","volume":"7","author":"Haga","year":"2016","journal-title":"Small GTPases"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1083\/jcb.201612069","article-title":"Rho GTPase signaling complexes in cell migration and invasion","volume":"217","author":"Lawson","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Hudson, L.G., Gillette, J.M., Kang, H., Rivera, M.R., and Wandinger-Ness, A. (2018). Ovarian Tumor Microenvironment Signaling: Convergence on the Rac1 GTPase. Cancers, 10.","DOI":"10.3390\/cancers10100358"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5445","DOI":"10.1158\/0008-5472.CAN-17-1456","article-title":"The Rac GTPase in cancer: From old concepts to new paradigms","volume":"77","author":"Kazanietz","year":"2017","journal-title":"Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Aspenstr\u00f6m, P. (2018). Activated Rho GTPases in Cancer-The Beginning of a New Paradigm. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123949"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1158\/0008-5472.CAN-18-0619","article-title":"Targeting Rac and Cdc42 GTPases in Cancer","volume":"78","author":"Maldonado","year":"2018","journal-title":"Cancer Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.critrevonc.2018.01.012","article-title":"Relevance of small GTPase Rac1 pathway in drug and radio-resistance mechanisms: Opportunities in cancer therapeutics","volume":"124","author":"Cardama","year":"2018","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.7150\/jca.24824","article-title":"Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis","volume":"9","author":"Lou","year":"2018","journal-title":"J. Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s12032-014-0329-5","article-title":"Rac1 expression in epithelial ovarian cancer: Effect on cell EMT and clinical outcome","volume":"32","author":"Leng","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.3892\/ijo.2017.4093","article-title":"Rho GTPases as therapeutic targets in cancer (Review)","volume":"51","author":"Cardama","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1517\/17460441.2015.1058775","article-title":"Approaches of targeting Rho GTPases in cancer drug discovery","volume":"10","author":"Lin","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"123","DOI":"10.4161\/21541248.2014.973749","article-title":"The dynamics of Rho GTPase signaling and implications for targeting cancer and the tumor microenvironment","volume":"6","author":"Pajic","year":"2015","journal-title":"Small GTPases"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1038\/onc.2016.473","article-title":"Rho GTPases: Anti- or Pro-Neoplastic Targets?","volume":"36","author":"Zandvakili","year":"2017","journal-title":"Oncogene"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Smithers, C.C., and Overduin, M. (2016). Structural Mechanisms and Drug Discovery Prospects of Rho GTPases. Cells, 5.","DOI":"10.3390\/cells5020026"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1038\/onc.2016.323","article-title":"Epithelial-mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1\/2 and Src signaling pathways","volume":"36","author":"Fang","year":"2017","journal-title":"Oncogene"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"933","DOI":"10.3892\/ijo.2017.3853","article-title":"Rhein suppresses matrix metalloproteinase production by regulating the Rac1\/ROS\/MAPK\/AP-1 pathway in human ovarian carcinoma cells","volume":"50","author":"Zhou","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"8531","DOI":"10.1074\/jbc.M112.435941","article-title":"Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe","volume":"288","author":"Hong","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1158\/1538-7445.AM2018-3159","article-title":"Abstract 3159: Rac1 and Cdc42 as drivers in ovarian cancer metastasis","volume":"78","author":"Rivera","year":"2018","journal-title":"Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Luo, W., Friedman, M.S., Shedden, K., Hankenson, K.D., and Woolf, P.J. (2009). GAGE: Generally applicable gene set enrichment for pathway analysis. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-161"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Earp, M., Tyrer, J., Winham, S.J., Lin, H.-Y., Chornokur, G., Dennis, J., Aben, K.K., Anton-Culver, H., Antonenkova, N., and Bandera, E.V. (2018). Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197561"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Panigrahy, D., Gartung, A., Yang, J., Yang, H., Gilligan, M.M., Sulciner, M.L., Bhasin, S.S., Bielenberg, D.R., Chang, J., and Schmidt, B.A. (2019). Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases. J. Clin. Investig., 130.","DOI":"10.1172\/JCI127282"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.ejmech.2016.11.038","article-title":"1,2,3-Triazolyl ester of Ketorolac: A \u201cClick Chemistry\u201d-based highly potent PAK1-blocking cancer-killer","volume":"126","author":"Nguyen","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"300","DOI":"10.5582\/ddt.2017.01058","article-title":"Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis in ovo (fertilized eggs) via their common PAK1-survivin\/VEGF signaling pathway","volume":"11","author":"Ahn","year":"2017","journal-title":"Drug Discov. Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/8\/1049\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:09:17Z","timestamp":1760188157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/8\/1049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,24]]},"references-count":128,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["cancers11081049"],"URL":"https:\/\/doi.org\/10.3390\/cancers11081049","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,24]]}}}