Ultra-high dose oralω3 docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) block tumorigenesis in a MYCN-driven neuroblastoma model

Background/Objectives Neuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk disease is highly genotoxic. This, combined with less than 50% survival in high-risk disease and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential. Methods A prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wild-type mice were gavaged with 12.3-14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6-6.0 g/d arachidonic acid (ARA). At seven days, MYCN -expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10-20 d post-injection when tumors and tissues were harvested. Results Fifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n=8 or 10 animals. In contrast, ω6 arachidonic acid (4.6-6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days)compared to control. Co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism. Conclusions Sustained high dose ω3 (weeks/months) is safe and well tolerated in humans. These results suggest that ω3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma. Simple Summary Pediatric Neuroblastoma has an overall mortality rate above 50%, and the current standard of care consists of highly genotoxic compounds. The biological actions of omega-6 (ω6) and omega-3 (ω3) highly unsaturated fatty acids (HUFA) generally oppose one another with the ω6 HUFA signaling for inflammation and angiogenesis (new blood vessel formation). Prolonged use of ultrahigh dose (15-20 g/d) ω3 HUFA has shown efficacy in catastrophic human traumatic brain injury and is well tolerated. Tumors form in about 50% of mice in our pediatric neuro-blastoma model. We show that 12-14 g/d adult human equivalent doses of ω3 EPA or DHA, as well as an oxidation-resistant form of DHA (D-DHA), completely block tumor formation, whereas a dose of about 5 g/d of ω6 ARA enhances tumorigenesis. Our data suggest that ultra-high dose ω3 therapy should be carefully investigated as a low-toxicity approach to neuroblastoma intervention.