title: Addition of DHA Synergistically Enhances the Efficacy of Regorafenib for Kidney Cancer Therapy.
abstract: Kidney cancer is the sixth most common cancer in the United States, and its incidence is increasing. The treatment of this malignancy took a major step forward with the recent introduction of targeted therapeutics, such as kinase inhibitors. Unfortunately, kinase inhibition is associated with the onset of resistance after 1 to 2 years of treatment. Regorafenib, like many multikinase inhibitors, was designed to block the activities of several key kinase pathways involved in oncogenesis (Ras/Raf/MEK/ERK) and tumor angiogenesis (VEGF-receptors), and we have recently shown that it also possesses soluble epoxide hydrolase (sEH) inhibitory activity, which may be contributing to its salutary effects in patients. Because sEH inhibition results in increases in the DHA-derived epoxydocosapentaenoic acids that we have previously described to possess anticancer properties, we asked whether the addition of DHA to a therapeutic regimen in the presence of regorafenib would enhance its beneficial effects in vivo We now show that the combination of regorafenib and DHA results in a synergistic effect upon tumor invasiveness as well as p-VEGFR attenuation. In addition, this combination showed a reduction in tumor weights, greater than each agent alone, in a mouse xenograft model of human renal cell carcinoma (RCC), yielding the expected oxylipin profiles; these data were supported in several RCC cell lines that showed similar results in vitro Because DHA is the predominant component of fish oil, our data suggest that this nontoxic dietary supplement could be administered with regorafenib during therapy for advanced RCC and could be the basis of a clinical trial. Mol Cancer Ther; 15(5); 890-8. ©2016 AACR.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.affiliation: Department of Entomology, University of California, Davis, California.
authors.forename: Debin
authors.initials: D
authors.lastname: Wan
authors.affiliation: Department of Entomology, University of California, Davis, California.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology, University of California, Davis, California. Cancer Center, University of California, Davis, California.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, California. Cancer Center, University of California, Davis, California. Medical Service, Sacramento VA Medical Center, Sacramento, California. rhweiss@ucdavis.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D003687:Dehydroepiandrosterone; D003577:Cytochrome P-450 Enzyme System