(31-05-13) UC Davis Researchers: Key Discovery Involving Omega-3 Fatty Acids and Cancer

Guodong Zhang in his lab. (Photo by Kathy Keatley Garvey)
DAVIS--Researchers at the University of California, Davis have discovered a key mechanism by which dietary omega-3 fatty acids (fish oils) could reduce the tumor growth and spread of cancer, a disease that kills some 580,000 Americans a year.
In groundbreaking research, the team of 16 scientists led by Dr. Guodong Zhang of the Bruce Hammock laboratory, Department of Entomology and the UC Davis Comprehensive Cancer Center, discovered cytochrome P450 epoxygenase metabolites of omega-3 fatty acid DHA or epoxy docosapentaenoic acids (EDPs) block blood supply to the tumor and thus inhibit tumor growth and metastasis.
The natural EDPs were further stabilized by a drug called a soluble epoxide hydrolase inhibitor which is already under development to control pain and hypertension. The research was published April 3 in the Proceedings of the National Academy of Sciences (PNAS).
“Many human studies have shown that omega-3 fatty acids reduce the risks of cancers, but the mechanism is poorly understood,” said Zhang, a postdoctoral researcher. “Our study provides a novel mechanism by which these omega-3 lipids inhibit cancer.”
“We demonstrated that EDPs have very potent anti-cancer and anti-metastatic effects,” Zhang said. “Current anti-cancer drugs that block angiogenesis (the formation of new blood vessels to fuel tumor progression) can cause serious side effects such as hypertension. By blocking angiogenesis by a new mechanism and by widening blood vessels, EDPs could block tumor growth with reduced side effects in cancer patients.”

Lisa Mahakian, Katherine Ferrara and Xiaowen Hu. (Photo Courtesy of the UC Davis College of Engineering)
The studies, conducted on mice, also suggest that a combination of omega-3 diet and some anti-cancer drugs such as sorafenib, “could not only be efficacious to treat cancers but reduce potential side effects,” Zhang said.
Co-author Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center, said the research shows lots of promise. “Basically what Dr. Zhang and his collaborators found is that the epoxides of the omega 3 fatty acid DHA are strongly anti-angiogenic and block tumor growth and metastasis. He used the soluble epoxide hydrolase inhibitors to stabilize these epoxides in mice. In contrast, the epoxides of the omega 6 fatty acid ARA (arachidonate) are mildly angiogenic and encourage tumor and wound healing.”
“Thus the effects of the soluble epoxide hydrolase inhibitors have opposite effects depending on whether the background lipid mediators are omega 3 or omega 6,” Hammock said. “Assuming that humans are mice (the study involved mice), the prediction is that with some cancer drugs--particularly the ones like sorafenib and regorafenib that are potent epoxide hydrolase inhibitors as well as anti-angiogenic agents--these could be more effective with a high omega 3 and low omega 6 background.”
Said co-author and chemist Sung Hee Hwang: “This is exciting work as a chemist to be involved in; not only was there a strong team of chemists, biochemists and analytical chemists working with Guodong, but we got the chance to collaborate with the bioengineers from the Katherine Ferrara laboratory who did the imaging as well as with some top cancer researchers from UC Davis and Harvard.”

Four global experts who were not involved with the research, “Epoxy Metabolites of Docosahexaenoic acid (DHA) Inhibit Angiogenesis, Tumor Growth and Metastasis,” were asked for comment.
“This is an exciting step towards our full appreciation of the impact of bioactive products from the DHA metabolome,” said Charles Serhan of Harvard Medical School, an expert on omega-3 autacoids and inflammation who is the Simon Gelman Professor of Anesthesia, Periopterative and Pain Medicine, Harvard Medical School. “This (UC Davis) contribution places metabolic conversion of omega-3 DHA to epoxy DHA products pivotal in vascular mechanisms key in cancer and vascular biology. It will be exciting to watch these important findings translated to humans for new evidence based treatments for angiogenesis, tumor growth and cancer metastasis.”
Cardiologist Jonathan Lindner of the Oregon Health & Science University lauded the research.

“New drug strategies for fighting cancer could emerge from knowledge of how the body uses nutrition to promote health,” Lindner said. “Diet has been shown to influence susceptibility to many types of cancer, and also to influence rate of tumor progression and response to chemotherapy. This information has been leveraged to make reasonable recommendations on diet in patients with cancer. Perhaps more importantly, by uncovering how diet influences tumor development and growth, it may be possible to develop new drugs that work through the same beneficial pathways.”
“The study by Zhang and colleagues has uncovered a previously unrecognized anti-cancer effect of omega-3 fatty acids which are an important lipid component of diets that have been developed to prevent heart disease and cancer,” Lindner said. “The authors have demonstrated that metabolites of these lipids can act to suppress the growth of new blood vessels that are necessary to feed tumor growth. By shutting off the tumor’s blood supply, these compounds can act to dramatically slow tumor growth and prevent metastasis. The results from this suggest that new drug strategies for fighting cancer could emerge from knowledge of how the body uses nutrition to promote health.”

Bruce Hammock
Professor Ingrid Fleming of the Institute for Vascular Signalling, Center for Molecular Medicine at the Goethe University, Frankfurt, Germany, described the study as “exciting” and offering great potential. “Inhibitors of the soluble epoxide hydrolase (sEH) have potential benefits for the prevention of the metabolic syndrome and the associated cardiovascular complications,” said Fleming. “However, interest in the development of these compounds for therapy has been limited by the fact that increased levels of the epoxides of arachidonic acid promote angiogenesis and thus increase tumor growth and metastasis.”
“Now UC Davis researchers report that the epoxides of docosahexaenoic acid do exactly the opposite by inhibiting angiogenesis, and thus decrease tumor growth and metastasis,” Fleming said. “Thus, it may now be possible to potentate the beneficial effects of sEH inhibition by supplementing therapy with dietary omega-3 fatty acids.”
Lois Smith, professor of ophthalmology at the Harvard Medical School and Boston Children’s Hospital, commented: “Fish oil (enriched in ù3 polyunsaturated fatty acids; ù3-PUFAs) has been shown to reduce the occurrence of diseases associated with abnormal vessel development such as age-related macular degeneration and retinopathy of prematurity. In this study, Zhang et al. demonstrate that epoxydocosapentaenoic acids (EDPs), the metabolites of ù3-PUFA by cytochrome P450 enzymes inhibits vessel development in tumors and suppresses tumor growth and metastasis by reducing VEGF-C production. This discovery provides a novel mechanism of ù3-PUFAs action on vessels and tumors and may lead to new therapies.”
Zhang, who focuses his research on lipid mediators on angiogenesis, tumor growth and metastasis, received his doctorate in food science from the University of Wisconsin-Madison.
Cancer, characterized by uncontrolled growth and spread of abnormal cells, can be caused by external factors such as tobacco, infectious organisms, chemicals and radiation, and by internal factors such as inherited mutations, hormones, immune conditions and mutations that occur from metabolism, according to the National Cancer Institute. Death occurs when the cancer is not controlled. Some 1.6 million new cases of cancer are expected to be diagnosed this year. Cancer, the second most common cause of death in the United States, is exceeded only by heart disease.
Other co-authors of the paper in addition to Hammock were Jun Yang, Jun-Yan Liu, King Sing Stephen Lee, Arzu Ulu, and Sung Hee Hwang, all of the UC Davis Department of Entomology and UC Davis Comprehensive Cancer Center; Lisa Mahakian, Xiaowen Hu, Katherine Ferrara, Sarah Tam, and Elizabeth Ingham, UC Davis Department of Biomedical Engineering; Hiromi Wettersten of the UC Davis Division of Nephrology, Department of Internal Medicine; Robert Weiss, Comprehensive Cancer Center, Division of Nephrology and U.S. Department of Veterans’ Affairs Medical Center, Sacramento; and Dipak Panigrahy and Mark Kieran of the Vascular Biology Program, Children’s Hospital, Harvard Medical School.
The research project received funding support from the National Institute on Environmental Health Sciences Superfund (Bruce Hammock); UC Davis Research Investments in the Sciences and Engineering (RISE) Program (Katherine Ferrara); NIH research grant (Dipak Panigrahy); Stop and Shop Pediatric Brain Tumor Fund and the C. J. Buckley Pediatric Brain Tumor Fund (Mark Kieran); and the Medical Service of the U.S. Department of Veterans’ Affairs (Robert Weiss). Hammock is a George and Judy Marcus Senior Fellow of the American Asthma Society.

Sources: (Editor's Note: News embargo lifted at 12 noon, April 1, Pacific Daylight Time. The research paper was posted on the PNAS website April 3.)
April 1, 2013
Link to PNAS Paper
National Institute of Environmental Health Science (NIEHS) website

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