Leukotriene B4 Receptor Antagonist LY293111 Inhibits Proliferation and Induces Apoptosis in Human Pancreatic Cancer Cells

• Published in: Clinical cancer research 2002-10, Vol.8 (10), p.3232-3242
• Main Authors: TONG, Wei-Gang, DING, Xian-Zhong, HENNIG, Rene, WITT, Richard C, STANDOP, Jens, POUR, Parviz M, ADRIAN, Thomas E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Benzoates - pharmacology; Biological and medical sciences; Blotting, Western; Cell Division - drug effects; Chemotherapy; Female; Humans; In Situ Nick-End Labeling; In Vitro Techniques; Leukotriene B4 - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Microscopy, Polarization; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Neoplasm Transplantation; Neoplasms, Experimental; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Receptors, Leukotriene B4 - antagonists & inhibitors; Receptors, Leukotriene B4 - genetics; Receptors, Leukotriene B4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

Purpose: The effects of leukotriene (LT) B4 and its receptorantagonist 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.