The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo
Authors: Dayna R Dominguez
S Ray Kenney
Yuna Guo
Angela Wandinger-Ness
Laurie G Hudson
Martha M Grimes
Kathryn J Brayer
Journal: BMC Cancer (2021)
Discipline: CLINICAL MEDICINE
Keywords: Cdc42; Gene expression; Ketorolac; Ovarian cancer; RNA-seq
Affiliations: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA. ., Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA., Division of Molecular Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA., Analytical and Translational Genomics Shared Resource, Comprehensive Cancer Center, University of New Mexico, Albuquerque, New Mexico, USA., Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA., Department of Pathology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA.

Abstract:  Background: Rho-family GTPases, including Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42), are important modulators of cancer-relevant cell functions and are viewed as promising therapeutic targets. Based on high-throughput screening and cheminformatics we identified the R-enantiomer of an FDA-approved drug (ketorolac) as an inhibitor of Rac1 and Cdc42. The corresponding S-enantiomer is a non-steroidal anti-inflammatory drug (NSAID) with selective activity against cyclooxygenases. We reported previously that R-ketorolac, but not the S-enantiomer, inhibited Rac1 and Cdc42-dependent downstream signaling, growth factor stimulated actin cytoskeleton rearrangements, cell adhesion, migration and invasion in ovarian cancer cell lines and patient-derived tumor cells. Methods: In this study we treated mice with R-ketorolac and measured engraftment of tumor cells to the omentum, tumor burden, and target GTPase activity. In order to gain insights into the actions of R-ketorolac, we also performed global RNA-sequencing (RNA-seq) analysis on tumor samples. Results: Treatment of mice with R-ketorolac decreased omental engraftment of ovarian tumor cells at 18 h post tumor cell injection and tumor burden after 2 weeks of tumor growth. R-ketorolac treatment inhibited tumor Rac1 and Cdc42 activity with little impact on mRNA or protein expression of these GTPase targets. RNA-seq analysis revealed that R-ketorolac decreased expression of genes in the HIF-1 signaling pathway. R-ketorolac treatment also reduced expression of additional genes associated with poor prognosis in ovarian cancer. Conclusion: These findings suggest that R-ketorolac may represent a novel therapeutic approach for ovarian cancer based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor. R-ketorolac modulates relevant pathways and genes associated with disease progression and worse outcome. 

Retracted: No

PubPeer comments:
 The same authors concluded once more in their new publication that R-ketorolac may represent a novel therapeutic approach for ovarian cancer based on its pharmacologic activity as a Rac1 and Cdc42 inhibitor. R-ketorolac modulates relevant pathways and genes associated with disease progression and worse outcome. There is no evidence for its inhibitory activity against either GTPase. Figure 1 makes the claim of inhibitory activity of R-ketorolac against Rac1 and Cdc42 without any new data, rather referencing u201cR-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasisu201d Molecular Cancer Therapeutics (2015) pubmed: 26206334 doi: 10.1158 1535-7163.mct-15-0419. The authors could have easily compared u201cRu201d to u201cSu201d-ketorolac since the later is found to be inactive against Rac1 and Cdc42; we assume they did and found similar results. These authors keep misleading the field with their new publication concluding that R-ketorolac reduces ovarian cancer tumor burden in vivo; but Figure 3B hardly support this conclusion; yes there was a little reduction but the ovarian cancer remains intact overall.  ,