Abstract 2454: Omega-3 fatty acids DHA and EPA decrease oncogenic PGE2 in medulloblastoma in vitro and in vivo

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Abstract Background: The embryonic brain tumor medulloblastoma is a highly malignant tumor of the cerebellum and the most common CNS malignancy of childhood. By combining neurosurgery, chemotherapy and radiation overall survival is about 70% but the intensive treatment regimen often leads to severe neurological sequelae and the risk of resistant relapses is significant. Hence, there is a need to improve treatment to reduce and alleviate late side effects. Inflammation plays an important role in the tumor microenvironment by suppressing immune response, promoting angiogenesis, facilitating tumor invasion, and metastasis. Prostaglandin E2 (PGE2) is a pro-inflammatory lipid mediator derived from the omega-6 fatty acid arachidonic acid (AA) through conversion by the key enzymes COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Previous work from our group showed that medulloblastomas express high levels of COX-2 and mPGES-1 as well as all four PGE2 receptors (EP1-4) and most importantly that PGE2 promotes tumor proliferation. The ω-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) show anti-inflammatory characteristics in general and exert anti-tumoral properties in several cancer types. Here we investigate the potential role of DHA and EPA in treatment of medulloblastoma and their effect on prostaglandins in vitro and in vivo. Methods: In six medulloblastoma cell lines the cytotoxic activity of DHA and EPA was analyzed using cell viability assays. PGE2 levels were assessed in three medulloblastoma cell supernatants after 24 hrs of DHA treatment by ELISA. The prostaglandins were evaluated in human medulloblastoma xenografts in nude mice treated with DHA or a combination of DHA and EPA for 30 days from time of tumor take. Control mice were fed with normal chow. The levels of prostaglandins in the tumor tissue were analyzed with LC-MS/MS. Furthermore, the incorporation of fatty acids in tumors, erythrocytes and brain tissue was analyzed with GC-MS/MS. Results: Both DHA and EPA exerted cell toxicity in a dose dependent manner in vitro. DHA reduced the PGE2 production in all three cell lines investigated. In vivo, the treatment with DHA alone and the combination of DHA and EPA significantly increased the omega-3 index in tumors, erythrocytes and normal brain. The PGE2, and prostacyclin was significantly reduced in both treatment groups while thromboxane levels remained unchanged. The in vivo treatment was non-toxic. Conclusions: Lowering the pro-inflammatory PGE2 levels could mitigate the ongoing inflammation in the tumor microenvironment. We show that the omega-3 fatty acids DHA and EPA exert toxic effects on medulloblastoma cells in vitro and reduce PGE2 both in vitro and in vivo. We propose that DHA and EPA are interesting candidates to improve current medulloblastoma therapy. Citation Format: Linda Ljungblad, Filip Bergqvist, Teodora Andonova, Per-Johan Jakobsson, John Inge Johnsen, Per Kogner, Malin Wickström. Omega-3 fatty acids DHA and EPA decrease oncogenic PGE2 in medulloblastoma in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2454.