Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells

Purpose: The effects of leukotriene (LT) B4 and its receptor antagonist LY293111 on proliferation and Apoptosis of human pancreatic Cancer cells were investigated, both in vitro and in vivo.

Experimental design: Six human pancreatic Cancer cell lines (MiaPaCa-2, HPAC, Capan-1, Capan-2, PANC-1, and AsPC-1) were used. Expression of LTB4 receptors, BLT1 and BLT2, was measured by reverse transcription-PCR. Cell proliferation was measured by [methyl-(3)H]thymidine incorporation and cell number counting. Extracellular signal-regulated kinase (ERK) 1/2 activation was measured by Western blotting. Apoptosis was assessed by morphology, terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and poly(ADP-ribose) polymerase cleavage. The effect of LY293111 on growth of AsPC-1 and HPAC cell xenografts was assessed in BALB/c nu/nu athymic mice.

Results: Both LTB4 receptor types were found to be expressed in human pancreatic Cancer cells. The LTB4 receptor antagonist LY293111 caused both time- and concentration-dependent inhibition of proliferation of all six human pancreatic Cancer cell lines studied. In contrast, LTB4 stimulated proliferation of these cell lines and induced ERK1/2 phosphorylation. The growth-stimulatory effect and ERK1/2 phosphorylation induced by LTB4 were inhibited by LY293111. Coincident with growth inhibition, LY293111 induced Apoptosis in these pancreatic Cancer cell lines, as indicated by morphology, TUNEL assay, and poly(ADP-ribose) polymerase cleavage. In studies using AsPC-1 and HPAC cell xenografts in athymic mice, LY293111 treatment markedly inhibited tumor growth over a 24-day treatment period, as measured by both tumor volume and tumor weight. In situ tissue TUNEL assay showed massive Apoptosis in LY293111-treated tumor tissues.

Conclusions: LTB4 can directly regulate the growth of human pancreatic Cancer cells and control their survival. Additional studies will clarify the underlying mechanisms of LTB4-regulated pancreatic Cancer cell growth and Apoptosis. LTB4 receptor blockade and inhibition of the downstream signal pathway are likely to be valuable for the treatment of human pancreatic Cancer.