Researchers at UC Davis have shown that docosahexaenoic acid (DHA), a fatty acid commonly found in fish and fish oil supplements, reduces renal cell carcinoma invasiveness, growth rate, and blood vessel growth when combined with the anti-cancer therapy regorafenib. The study was published in the May issue of the journal Molecular Cancer Therapeutics.
“Most renal cell carcinomas learn to escape therapy after a couple of years,” said Robert Weiss, professor of medicine at UC Davis, chief of nephrology at Sacramento VA Medical Center, and head of the kidney cancer working group at the UC Davis Comprehensive Cancer Center. “A simple additive, which is completely nontoxic, could have a positive effect on disease, even rescuing regorafenib and similar therapies from resistance.”
Regorafenib is one of a new generation of anti-cancer therapies that attack tyrosine kinases – enzymes that activate other proteins. Unfortunately, kidney cancers mutate to resist these therapies.
From their previous work, Weiss and colleagues knew that DHA metabolites, called epoxydocosapentaenoic acid (EDP), have the potential to restrain the ability of cancers to invade and grow blood vessels. The problem was an enzyme called soluble epoxide hydrolase (sEH), which breaks down and inactivates EDP. The study found that DHA and regorafenib are greater than the sum of their parts.
“We knew that regorafenib blocks sEH,” said Weiss. “If you add more DHA and block sEH, all that DHA goes towards creating EDP, which contributes to the anti-cancer effect.”
To see whether DHA complemented regorafenib, researchers tested the combination against both cancer cell lines and human tumors in mice. They found that combining these compounds killed kidney cancer cells in both models.
In particular, the combination reduced tumor growth and angiogenesis, the process by which tumors recruit blood vessels to feed their expansion. Specifically, these agents targeted the MAP/ERK kinase, which contributes to tumor growth, and the VEGFR protein, which controls blood vessel development.
Though the results are encouraging, Weiss cautions that these benefits are quite narrow, relying on the synergistic interaction between regorafenib and DHA. In other words, there’s no proof that taking fish oil supplements or eating fish like salmon would have any impact against kidney cancer on their own.
“We don’t have any evidence for that so far,” said Weiss. “It would be premature to make that assumption.”
But he said the findings do highlight a relatively simple way patients with advanced kidney cancer could increase the effectiveness of their treatment. The next step will be to combine regorafenib and fish oil in patients.
“We would like to have oncologists implement this in the clinic,” said Weiss. “It’s an easy thing to tell your patient to take fish oil.”
Other authors included Jeffrey Kim, Arzu Ulu, Debin Wan, Jun Yang and Bruce D Hammock.
This research was funded by NIH grants 1R01CA135401-01A1,1R03CA181837-01and 1R01DK082690-01A; the Medical Service of the US Department of Veterans’ Affairs,and Dialysis Clinics, Inc., NIEHS R01 ES002710 and NIEHS Superfund Program P42 ES004699.
For more information about the UC Davis Comprehensive Cancer Center please visit http://www.ucdmc.ucdavis.edu/cancer/