The Role of PPARγ Receptors and Leukotriene B₄ 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 B4 receptor pathway and the PPARγ pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 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 PPARγ 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 LTB4 receptors and PPARγ.

Eicosanoids and cancer

“…The LTB 4 receptor antagonist, LY293111, significantly inhibits tumour growth and metastases in a fluorescent orthotopic model of pancreatic cancer71 and a mouse xenograft model of human CRC147. Unfortunately, the results from two Phase II trials showed that LY293111 did not improve progressionfree survival in patients with non-small-cell lung or pancreatic cancer148. In addition, a CysLT1 receptor antagonist, zafirlukast, reduced tumour burden in a mouse model of carcinogen-induced lung tumours149.…”

Regulation of inflammation in cancer by eicosanoids

“…The combination of the LTB 4 receptor antagonist, LY293111, and gemcitabine was most effective on tumor growth and metastases in an orthotopic model of pancreatic cancer (134). However, this combination did not improve progression-free survival in Phase II clinical trial of pancreatic cancer or non-small-cell lung cancer (135). Another pro-inflammatory mediator derived from 5-LOX metabolism of the arachidonic acid cascade is leukotriene D 4 (LTD 4 ).…”

Peroxisome proliferator-activated receptors and cancer: challenges and opportunities

“…Several cellular studies demonstrate that PPARγ activation decreases pancreatic cancer cell growth and attenuates their migration and invasive capacity (Motomura et al ., 2000; Toyota et al ., 2002; Tsujie et al ., 2003; Motomura et al ., 2004; Adrian et al ., 2008; Kumei et al ., 2009). Using a pancreatic carcinoma xenograft model of nude mice, it was reported that PPARγ activation inhibited pancreatic cancer growth and suppressed tumour angiogenesis (Dong et al ., 2009).…”