Lipid mediators in the prevention and therapy of neuroblastoma

Neuroblastoma is a cancer of the nervous system that mainly affects infants and young children. It is the most common solid extracranial tumor of childhood, and accounts for almost 10% of all childhood cancer deaths. Despite intense multimodal treatment consisting of surgery, chemotherapy, radiotherapy, and stem cell rescue, survival is only 50% in the high-risk group, and the overall survival is around 70%. We therefore need to improve existing treatment protocols and search for new medications.

Inflammation drives cancer growth and targeted therapy that dampens inflammatory responses is anti-proliferative. We have previously shown that the inducible COX-2 enzyme that converts the omega-6 fatty acid arachidonic acid (AA) to various inflammatory prostaglandins is upregulated in neuroblastoma tissue. We have also shown that celecoxib, a selective inhibitor of COX-2, may inhibit neuroblastoma growth.

This thesis shows that celecoxib both prevents tumor formation and reduces tumor growth in a neuroblastoma xenograft rat model. In addition, celecoxib enhances the effect of the chemotherapeutic drugs irinotecan and doxorubicin. By immunohistochemistry, we detected reduced proliferation and inhibited angiogenesis in tumors from animals treated with celecoxib, either by gavage or by an enriched diet.

Omega-3 fatty acids oppose the effects of omega-6 fatty acids such as AA and have been implicated in cancer treatment and prevention. Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are precursors of anti-inflammatory compounds. From EPA, a different series of prostaglandins are produced, and from DHA, resolvins and protectins are produced, which are potent pro-resolving lipid mediators essential for the clearance of inflammatory cells and mediators at an injured site.

In this thesis I show that DHA is toxic to neuroblastoma cells both in vivo and in vitro. In vivo, DHA is able to delay time to tumor development and reduce tumor growth in neuroblastoma xenograft models. In vitro, DHA acts by inducing mitochondrial-dependent apoptosis. We also show that neuroblastoma cells convert DHA to hydroperoxy and hydroxy fatty acids through both enzymatic and non-enzymatic mechanisms. However, DHA is not converted to resolvins or protectins in neuroblastoma cells. DHA also potentiates the effect of other cytotoxic drugs such as chemotherapeutics, arsenic trioxide, and non-steroidal anti-inflammatory drugs (NSAIDs).

In summary, this thesis shows that inhibiting the omega-6 fatty acid pathway and enhancing the omega-3 fatty acid pathway are both possible new strategies for neuroblastoma treatment, and suggests these compounds to be tested as novel therapy for children with neuroblastoma in clinical trials.

List of scientific papers

I. Lindskog M, Gleissman H, Ponthan F, Castro J, Kogner P, Johnsen JI (2006). Neuroblastoma cell death in response to docosahexaenoic acid: sensitization to chemotherapy and arsenic-induced oxidative stress. Int J Cancer. 118(10): 2584-93
https://pubmed.ncbi.nlm.nih.gov/16353135

II. Ponthan F, Wickström M, Gleissman H, Fuskevåg OM, Segerström L, Sveinbjörnsson B, Redfern CP, Eksborg S, Kogner P, Johnsen JI (2007). Celecoxib prevents neuroblastoma tumor development and potentiates the effect of chemotherapeutic drugs in vitro and in vivo. Clin Cancer Res. 13(3): 1036-44
https://pubmed.ncbi.nlm.nih.gov/17289900

III. Gleissman H, Yang R, Martinod K, Lindskog M, Serhan CN, Johnsen JI, Kogner P (2009). Docosahexaenoic acid metabolome in neural tumors: Identification of cytotoxic intermediates. [Submitted]

IV. Gleissman H, Segerström L, Hamberg M, Ponthan F, Lindskog M, Johnsen JI, Kogner P (2009). Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo. [Manuscript]