Institutionen för kvinnors och barns hälsa / Department of Women's and Children's Health
Abstract
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