Cyclooxygenases and lipoxygenases as potential targets for treatment of pancreatic cancer.

Pancreatic adenocarcinoma is characterized by poor prognosis, late diagnosis and lack of response to conventional therapies. The incidence of this disease shows no sign of declining in the Western world. Thus, new targets need to be identified for pancreatic cancer treatment. In particular, new chemotherapeutic agents would be extremely beneficial for control of unresectable cancer and metastatic lesions as well as for prevention of this deadly disease. Mounting evidence suggests that both lipoxygenases (LOXs) and cyclooxygenases (COXs), the key enzymes for arachidonic acid metabolism, have a profound influence on the development and progression of several human cancers. Recent evidence suggests that both COX and LOX pathways are important in pancreatic cancer. Results from immunocytochemical, RT-PCR, and Western blotting studies have shown that COX, specifically COX-2, is upregulated in human pancreatic cancer cell lines as well as human pancreatic cancer tissues compared with normal ductal cells and normal pancreas specimens. Agents that block COX enzymes significantly inhibit pancreatic cancer growth both in vitro and in vivo, in parallel with induction of apoptosis. Expression of both 5-LOX and 12-LOX is also seen in pancreatic cancer, although compared to the expression of COX this has not been extensively investigated. Chemical inhibitors or antisense oligonucleotides that block either 5-LOX or 12-LOX cause marked inhibition of pancreatic cancer cell proliferation. On the other hand, LOX metabolites stimulate growth of the tumor cells and reverse LOX-inhibitor-induced growth inhibition, suggesting the specific role of LOX in regulating pancreatic cancer cell proliferation. Although questions still need to be answered, such as the underlying mechanisms for COX and LOX-induced growth inhibition, both COX and LOX pathways are potential targets for pancreatic cancer treatment and chemoprevention. COX and LOX enzyme inhibitors are available and have been shown to be relatively safe in the treatment of other diseases.