Omega-3 docosahexaenoic acid is toxic to neuroblastoma in vitro and in vivo

529 Introduction: Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid found in fatty fish and marine oils. In humans it is the most abundant fatty acid in the membranes of brain and retinal cells, and is crucial for perinatal development of nervous tissues. DHA has been implicated in the prevention and treatment of various conditions such as cardiovascular, neurologic and inflammatory diseases, depression, ADHD, and malignancies. Epidemiologic studies show that high fish consumption is correlated with a lower incidence of cancer in the population. DHA has been reported to attenuate weight loss, increase appetite, improve quality of life and prolong survival in cancer patients. This indicates that DHA may be used in both prevention and treatment of cancer. Methods: We investigated if supplementation of DHA alone, or in combination with cytotoxic agents, could affect neuroblastoma (NB) cell growth in vitro by measuring cell cycle distribution, cell survival, clonogenicity, mitochondrial membrane potential and production of reactive oxygen species (ROS). In addition, xenograft tumor growth was monitored in rats receiving a DHA-enriched diet either prior to tumor cell injection or after establishment of macroscopic NB tumors. Rats were also randomized to receive DHA through gavage. Results: DHA induced dose- and time-dependent NB cell death and was associated with decreased clonogenic capacity, depolarization of the mitochondrial membrane potential, production of ROS and accumulation of DNA in sub-G1 phase of the cell cycle. DHA significantly enhanced the cytotoxicity of cisplatin, doxorubicin and irinotecan. DHA potently sensitized neuroblastoma cells to a clinically relevant concentration (1 µM) of arsenic trioxide (As2O3), and enhanced the effect of the non-steroidal anti-inflammatory drug diclofenac. Plasma levels of DHA were doubled in animals receiving DHA by gavage and increased by up to three fold in animals receiving the DHA-enriched diet. Tumor take was prevented or significantly delayed in the DHA-pretreated rats compared to rats on standard diet. Tumor growth was inhibited in rats receiving DHA by daily gavage compared to untreated controls. Conclusion: DHA alone is toxic to NB cells both in vitro and in vivo. The mechanisms of action involved may be suppression of eicosanoid biosynthesis, influences on transcription factor activity, and altered production of free radicals and ROS. These findings suggest that supplementation with the omega-3 fatty acid DHA may be a novel therapeutic approach for children with neuroblastoma.