The Role of PPARgamma Receptors and Leukotriene B(4) Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer

Abstract

Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B(4) receptor pathway and the PPARgamma pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B(4) receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPARgamma agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB(4) receptors and PPARgamma.

Figure 1

Immunocytochemistry of PPARγ receptor in normal human pancreas and in a PanIN lesion and a pancreatic cancer. The PPARγ receptor antibody shows a similar intensity of nuclear staining in normal ducts and in pancreatic cancer cells as well as cells in the PanIN lesion. In contrast, no staining is seen in normal islets, but nuclear staining is seen in islets from tissue adjacent to a cancer. These pictures are representative of eight samples of each tissue type. Staining was similar using antibodies from two different commercial sources.

Figure 2

Comparison of the effects of different concentrations of LY293111 and ciglitazone on proliferation of two human pancreatic cancer cell lines (Panc-1 and S2-013) after 24 and 96 hours of treatment, measured by thymidine incorporation. LY293111 was approximately 50 times more potent than ciglitazone at inhibiting proliferation of both cell lines. Data shown is mean±SEM from four separate experiments.

Figure 3

Effect of a PPARγ receptor antagonist, GW9662 on the inhibition of proliferation induced by LY293111 in AsPC-1 human pancreatic cancer cells after 24 hours of treatment. These cells express both the PPARγ receptor and LTB₄ (BLT1 and BLT2) receptors. While GW9662 alone was able to significantly increase thymidine incorporation, it was not able to block the inhibitory effect of different concentrations of LY293111.