Neuroblastoma is the most common pediatric extracranial solid tumor, characterized by heterogeneous clinical behaviors including maturation, regression, and aggressive growth. Currently, the overall survival of neuroblastoma patients is poor, which indicates a great need for new therapeutic approaches. We have previously shown that the dietary omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) inhibits proliferation of neuroblastoma cells, and that it enhances the cytotoxic effect of several chemotherapeutic agents. Further, we have shown that arsenic trioxide and non-steroidal anti-inflammatory drugs (NSAIDs) exert cytotoxic effects in neuroblastoma cells. In the present study we investigated if DHA could potentiate the cytotoxic effect of the above-mentioned substances. Moreover, we have evaluated the effects of combining DHA with retinoids, since retinoids are part of the standard treatment for children with high-risk neuroblastoma. Neuroblastoma cell lines were supplemented with DHA in combination with arsenic trioxide, diclofenac, or the retinoic acids 9-cis, 13-cis, RO13-6307, and fenretinide, and assessed for effects on cell viability. DHA potently sensitized neuroblastoma cells to a clinically relevant concentration (1μM) of arsenic trioxide. This effect could be inhibited by the radical scavenger vitamin E, indicating the involvement of radical oxygen species in the DHA- and arsenic-mediated tumor cell death. DHA exerted synergistic cytotoxic effects together with diclofenac, a pan-COX inhibitor, emphasizing the importance of a normal eicosanoid synthesis in tumor cell proliferation. Three of the retinoic acids tested, 9-cis, 13-cis and RO13-6307, antagonized the effect of DHA, while fenretinide promoted the DHA-induced cytotoxicity. These findings indicate that DHA can inhibit proliferation of neuroblastoma cells, and that this effect can be enhanced when DHA is combined with other substances such as arsenic trioxide, non-steroidal anti-inflammatory drugs and fenretinide.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]