ArticleMolecular cancer therapeutics2015
R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 110 citations in OpenAlex.
- Trial
- Prognostic Significance of Cdc42 Expression in Colorectal Cancer and Its Concordance Between Primary Tumors and Matched Metastases: A Retrospective Observational Study.Journal of clinical medicine · 2026Article
- Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury.International journal of biological sciences · 2026Article
- Targeting Cdc42: Novel Approaches in Cardiovascular Disorders.Current protein & peptide science · 2026Review
- Rac1 in gastric cancer: a molecular driver of invasion, EMT, and therapeutic resistance.Journal of translational medicine · 2025Review
- The Preservation of the Therapeutic Efficacy of the Secretome of Adipose Mesenchymal Stem Cells, Produced in the Presence of Antioxidant and Anti-Inflammatory Drugs.Pharmaceutics · 2025Article
- The Role of the p21-Activated Kinase Family in Tumor Immunity.International journal of molecular sciences · 2025Review
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- Regulation of Cancer Metastasis by PAK2.International journal of molecular sciences · 2024Review
- Article
- Oleate Promotes Triple-Negative Breast Cancer Cell Migration by Enhancing Filopodia Formation through a PLD/Cdc42-Dependent Pathway.International journal of molecular sciences · 2024Article
- Optical coherence tomography for multicellular tumor spheroid category recognition and drug screening classification via multi-spatial-superficial-parameter and machine learning.Biomedical optics express · 2024Article
- Intraoperative Ketorolac and Outcomes after Ovarian Cancer Surgery.Journal of clinical medicine · 2024Article
- A Recipe for Successful Metastasis: Transition and Migratory Modes of Ovarian Cancer Cells.Cancers · 2024Review
- Optical Coherence Tomography of Tumor Spheroids Identifies Candidates for Drug Repurposing in Ovarian Cancer.IEEE transactions on bio-medical engineering · 2023Article
- Potential treatments of COVID-19: Drug repurposing and therapeutic interventions.Journal of pharmacological sciences · 2023Review
- Ketorolac modulates Rac-1/HIF-1α/DDX3/β-catenin signalling via a tumor suppressor prostate apoptosis response-4 (Par-4) in renal cell carcinoma.Scientific reports · 2023Article
- Agent-based modeling predicts RAC1 is critical for ovarian cancer metastasis.Molecular biology of the cell · 2022Article
- Cytoskeletal and Cytoskeleton-Associated Proteins: Key Regulators of Cancer Stem Cell Properties.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Anesthetics and Long Term Cancer Outcomes: May Epigenetics Be the Key for Pancreatic Cancer?Medicina (Kaunas, Lithuania) · 2022Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion, and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high-throughput screening and computational shape homology approaches, we identified R-ketorolac as a Cdc42 and Rac1 inhibitor, distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip) and primary patient-derived ovarian cancer cells show that R-ketorolac is a robust inhibitor of growth factor or serum-dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small-molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration, and invasion. In summary, we provide evidence for R-ketorolac as a direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiologic responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA-approved drug, racemic ketorolac, that can be used in humans.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.