UC Davis and Harvard University scientists have found that a product resulting from a metabolized omega-3 fatty acid helps combat cancer by cutting off the supply of oxygen and nutrients that fuel tumor growth and spread of the disease.
Their work, in the Proceedings of the National Academy of Sciences, provides the first scientific evidence of the anti-cancer, anti-metastatic effects of the metabolite epoxy docosapentaenoic acid (EDP).
EDP is an endogenous compound produced by the human body from the omega-3 fatty acid docosahexaenoic acid (DHA) found in fish oil and breast milk.
In animal studies, the scientists found that EDP inhibits angiogenesis: the formation of new blood vessels in the body.
Tumors grow and spread by hijacking the normal biological process of angiogenesis, which plays a role in wound repair as well in growth and development.
By inhibiting angiogenesis, EDP reduces the growth and spread (metastasis) of tumors in mice, the researchers found.
EDP works by a different mechanism than many current anti-cancer drugs that block angiogenesis.
The researchers said that future studies hopefully will determine that stabilized EDP can be safely and effectively combined with other current anti-angiogenesis drugs in the treatment of cancer.
“As far as we know, EDPs are the first signaling lipids that have been discovered to have such potent anti-cancer effects,” said Guodong Zhang, the lead author of the article and a postdoctoral researcher in the laboratory of Bruce Hammock in the department of entomology and the UCD Comprehensive Cancer Center.
“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,” said Jonathan Lindner, professor of medicine at Oregon Health and Sciences University.
“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,” added Lindner, who was not involved in the study. “By shutting off a tumor’s blood supply, these compounds can act to dramatically slow tumor growth and prevent spread.
“The results from this study suggest that new drug strategies for fighting cancer could emerge from knowledge of how the body uses nutrition to promote health.”
The EDPs are broken down in the body by inhibiting the enzyme soluble epoxide hydrolase (sHI). In previous research, Hammock’s lab showed that inhibitors of the sEHI enzyme help to normalize physiological activity.
In the current study, the researchers determined that the addition of sEHI stabilized EDP in circulating blood, thereby producing anti-tumor effects.
The anti-cancer drugs sorafenib and regorafenib are FDA-approved sEHIs.
“It may be possible to improve the efficacy of these anti-cancer drugs by combining them with a diet high in omega-3 and low in omega-6 fatty acids,” Hammock said.
The researchers also found that a metabolite of arachidonic acid (ARA), an omega-6 fatty acid, has the opposite effect of EDP. The ARA metabolite, epoxyeicosatrienoic acids (EETs), slightly increases angiogenesis and tumor progression in mice.
“There is no free lunch,” said Katherine Ferrara, professor in the UCD department of biomedical engineering. “The EETs encourage wound healing, while the EDPs block the growth and metastasis of solid tumors.”
The scientists determined that EDP starves tumors by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2)-induced angiogenesis in mice. In laboratory cultures, EDP also suppresses the endothelial cell migration needed for new blood vessels.
Thus, EDP-based angiogenesis inhibitors offer an advantage over drugs that target the VEGF-VEGFR2 pathway, which increase patients’ risk for high blood pressure.
Because EDPs widen the blood vessels, a medication based on the new discovery should not increase the patient’s risk for high blood pressure.
— UC Davis Health News Office