The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo
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 cheminf...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-020-07716-1 |
| _version_ | 1818591484026290176 |
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| author | Martha M. Grimes S. Ray Kenney Dayna R. Dominguez Kathryn J. Brayer Yuna Guo Angela Wandinger-Ness Laurie G. Hudson |
| author_facet | Martha M. Grimes S. Ray Kenney Dayna R. Dominguez Kathryn J. Brayer Yuna Guo Angela Wandinger-Ness Laurie G. Hudson |
| author_sort | Martha M. Grimes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T10:13:10Z |
| format | Article |
| id | doaj.art-efb8e3d3ace141c5821b04d26f33cdf6 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-16T10:13:10Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-efb8e3d3ace141c5821b04d26f33cdf62022-12-21T22:35:32ZengBMCBMC Cancer1471-24072021-01-0121111610.1186/s12885-020-07716-1The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivoMartha M. Grimes0S. Ray Kenney1Dayna R. Dominguez2Kathryn J. Brayer3Yuna Guo4Angela Wandinger-Ness5Laurie G. Hudson6Department of Pharmaceutical Sciences, College of Pharmacy, University of New MexicoDepartment of Pharmaceutical Sciences, College of Pharmacy, University of New MexicoDepartment of Pharmaceutical Sciences, College of Pharmacy, University of New MexicoAnalytical and Translational Genomics Shared Resource, Comprehensive Cancer Center, University of New MexicoDepartment of Pathology, School of Medicine, University of New MexicoDepartment of Pathology, School of Medicine, University of New MexicoDepartment of Pharmaceutical Sciences, College of Pharmacy, University of New MexicoAbstract 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.https://doi.org/10.1186/s12885-020-07716-1Ovarian cancerKetorolacRho-family GTPaseRac1Cdc42Gene expression |
| spellingShingle | Martha M. Grimes S. Ray Kenney Dayna R. Dominguez Kathryn J. Brayer Yuna Guo Angela Wandinger-Ness Laurie G. Hudson The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo BMC Cancer Ovarian cancer Ketorolac Rho-family GTPase Rac1 Cdc42 Gene expression |
| title | The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| title_full | The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| title_fullStr | The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| title_full_unstemmed | The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| title_short | The R-enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| title_sort | r enantiomer of ketorolac reduces ovarian cancer tumor burden in vivo |
| topic | Ovarian cancer Ketorolac Rho-family GTPase Rac1 Cdc42 Gene expression |
| url | https://doi.org/10.1186/s12885-020-07716-1 |
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