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Mol Cancer Ther. 2015 Oct;14(10):2215-27. doi: 10.1158/1535-7163.MCT-15-0419. Epub 2015 Jul 23.

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis.

Author information

1
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico.
2
Cancer Center, University of New Mexico, Albuquerque, New Mexico. Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico.
3
Cancer Center, University of New Mexico, Albuquerque, New Mexico. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
4
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico.
5
Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
6
Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
7
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Cancer Center, University of New Mexico, Albuquerque, New Mexico. wness@unm.edu.

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.

PMID:
26206334
PMCID:
PMC4596774
DOI:
10.1158/1535-7163.MCT-15-0419
[Indexed for MEDLINE]
Free PMC Article

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