High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates,MYCN-driven tumorigenesisin vivo

Abstract

Neuroblastoma (NB) is a genetically diverse, highly metastatic pediatric cancer that accounts for an estimated 8% of childhood cancer incidence but is responsible for 15% of childhood cancer deaths. High-risk and relapsed cases have less than 50% and near 5% survival, respectively. The current standard of care is highly genotoxic, resulting in life-long health issues and an increased risk of new cancer incidence. Effective and less toxic approaches to neuroblastoma remain elusive. We show here that ω3 and ω6 highly unsaturated fatty acids (HUFA) have differential effects on tumor formation in a syngeneic model of neuroblastoma. We observe that 20 gram/d doses of ω3 DHA and EPA have a robust antitumor effect, wherein DHA and high-dose EPA completely abrogate tumor formation. In contrast, ω6 arachidonic acid (ARA) has the opposite effect, driving higher tumor penetrance and shorter latency. When used together, ARA and EPA treatment results in a reduced tumor burden analogous to the control group, indicating that EPA may directly oppose the mechanism of ARA-mediated tumor formation. ROS-resistant deuterated DHA (D-DHA), which has deuterium atoms in place of ordinary1H (protium) in the oxidatively labilebisallylic positions, also completely abrogated tumor formation, strongly suggesting that the mechanism of action is not through oxidation as might have been expected. Interestingly, despite high levels of fatty acid delivery, very little tissue accumulation was observed. These results suggest that high doses of ω3 HUFA DHA and EPA may represent a viable, low-toxicity avenue for neuroblastoma therapy.