Selective Inhibition Of Rac1 And Cdc42 In Ovarian Cancer Using The R-Enantiomer Of Ketorolac

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Ovarian cancer is the 5th leading cause of cancer death for women in the United States and is frequently diagnosed at late stage with multiple secondary metastases. Ras-homologous (Rho) family GTPases contribute to metastatic dissemination through regulation of actin reorganization, cell motility, cell-cell and cell-extracellular matrix adhesion. Rho GTPases are altered in a number of human cancers and our work provides the first evidence for dysregulation of Rac1 and Cdc42 in ovarian cancer. These findings suggest that Rac1 and Cdc42 inhibitors represent potential therapeutics for ovarian cancer. Using high throughput screening we identified the R-enantiomers of ketorolac and naproxen as novel inhibitors of Rac1 and Cdc42. Although it has been noted that R-enantiomers of nonsteroidal anti-inflammatory drugs are poor inhibitors of cyclooxygenase (COX) activity, little is known about the pharmacologic activities or targets of the R-enantiomers. The objective of this study was to investigate the effects of R-ketorolac on ovarian cancer. The effects of racemic, R- and S-ketorolac were investigated using SKOV3ip ovarian cancer cells. The compounds [NSC23766][1] and ML693334 were used as positive controls for Rac1 and Cdc42 respectively. An in vitro G-LISA assay indicated R-ketorolac, and not S-ketorolac, inhibits Rac1 and Cdc42 activity. In cells, R-Ketorolac, not S-ketorolac, inhibits cell:cell adhesion and cell migration. An intra-peritoneal xenograft model of tumor implantation was used to determine the effects of drugs in vivo. Racemic ketorolac decreased the number of implanted tumors by 70%. To elucidate the mechanism of GTPase inhibition by R-ketorolac, a targeted microarray analysis was performed. Preliminary results show an alteration to the gene expression profile of human cytoskeletal regulators in response to ketorolac treatment. These effects may be due to inhibition of Rac1 and Cdc42 directly or through upstream or downstream inhibition. This analysis also provides biomarkers that can be used to analyze tumor tissues from primary patients and animal studies. Together, these findings indicate that R-ketorolac is a novel inhibitor of Rac1 and/or Cdc42, and inhibit cellular processes necessary for ovarian cancer metastasis. The mechanism behind ketorolac inhibition will require further investigation. In the future, this drug may offer benefit to ovarian cancer patients through inhibition of these GTPase targets Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 910. doi:1538-7445.AM2012-910 [1]: /lookup/external-ref?link_type=GENPEPT&access_num=NSC23766&atom=%2Fcanres%2F72%2F8_Supplement%2F910.atom