TY - JOUR
T1 - A novel pharmacologic activity of ketorolac for therapeutic benefit in ovarian cancer patients
AU - Guo, Yuna
AU - Kenney, S. Ray
AU - Cook, Linda
AU - Adams, Sarah F.
AU - Rutledge, Teresa
AU - Romero, Elsa
AU - Oprea, Tudor I.
AU - Sklar, Larry A.
AU - Bedrick, Edward
AU - Wiggins, Charles L.
AU - Kang, Huining
AU - Lomo, Lesley
AU - Muller, Carolyn Y.
AU - Wandinger-Ness, Angela
AU - Hudson, Laurie G.
N1 - Funding Information:
This work is dedicated to the memory of Austin Hudson-LaPore. This study is supported by DOD OC110514 W81XWH-11-OCRP-TEA, UNM Science and Technology Corporation Gap Fund, Core Facility support (Flow Cytometry Shared Resource, Fluorescence Microscopy Shared Resource and Human Tissue Repository) from the University of New Mexico Cancer Research and Treatment Center (P30 CA118100). Focus Interactive Group grants from UNMCancer Center (0990MD; 0990Q8 to A.Wandinger-Ness and L.G. Hudson; 1146 to L. Cook). Contract HHSN261201300010I from the National Cancer Institute. Center for Molecular Discovery grants fromthe NIHMolecular Libraries Program (MH074425 and MH084690 to L.A. Sklar). NCI R25CA153825 (predoctoral fellowship to Y. Guo); INBRE NCRR 5P20RR016480 (predoctoral fellowship to S.R. Kenney).
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes. Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer'specific survival in ovarian cancer cases. Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the Renantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11-0.88). Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac.
AB - Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes. Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer'specific survival in ovarian cancer cases. Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the Renantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11-0.88). Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac.
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U2 - 10.1158/1078-0432.CCR-15-0461
DO - 10.1158/1078-0432.CCR-15-0461
M3 - Article
C2 - 26071482
AN - SCOPUS:84946818704
VL - 21
SP - 5064
EP - 5072
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -