The development of apoptosis activators offers a particularly appealing approach to the treatment of cancer. Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it was estimated that approximately 1.3 million new cases of cancer would have been diagnosed and 555,500 people would have died from cancer in the United States in 2002. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry. Pancreatic cancer is one type of cancer that is particularly in need of improved treatment options. Although pancreatic cancer only affects 0.01% of American (compared to 0.07% for lung cancer for example) mortality rates are high, principally due to the very low survival rates (only 4% of patients survive longer than 5 years following diagnosis compared to over 60% for all types of cancer.

Several studies have suggested that high dietary fat intake, particularly essential fatty acids, is associated with pancreatic cancer development and growth and it has previously been shown that blockade of either the 5-lipoxygenase or 12- lipoxygenase pathway of arachidonic acid metabolism inhibited pancreatic cancer cell proliferation and induced apoptosis. More recently, Northwestern University researchers have investigated the underlying mechanisms for lipoxygenase inhibitor-induced apoptosis and the potential of lipoxygenase inhibitors as antipancreatic cancer agents using the athymic mice xenograft model. Apoptosis of pancreatic cancer cells induced by lipoxygenase inhibitors was related to a reduction in the levels of antiapoptotic proteins Bcl-2 and Mcl-1 while that of the proapoptotic protein bax was increased. Lipoxygenase inhibitors also markedly induced the release of cytochrome c from mitochondria into the cytosol. Caspase-9, caspase-7, and caspase-3 but not caspase-8 were activated after treatment. In vivo studies in the athymic mice xenograft model also confirmed the growth inhibitory effect and induction of apoptosis by these lipoxygenase inhibitors in pancreatic cancer. About 20 inhibitors of 5- or 12-lipoxygenase are currently in development or on the market although their primary indication is usually airway or intestinal inflammation. In exception Eli Lilly’s LY-293111, an orally-available LTB4 receptor antagonist, 5-lipoxygenase inhibitor and PPARGamma agonist, is about to enter phase II evaluation for the treatment of pancreatic cancer. The data described here suggest that companies with an interest in lipoxygenase inhibitors may wish to evaluate them in models of pancreatic cancer.

Entry date January, 2003

Adapted from Tong et al, Mol Cancer Ther 2002 Sep;1(11):929-35 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct