l-663536 and Adenocarcinoma

Cyclooxygenase (COX)-2 and lipoxygenase (LOX)-5 are involved in carcinogenesis of pancreatic cancer. COX-2 inhibitor celecoxib displays inhibitory effects in pancreatic cancer cell growth. Recently, it has been reported that COX-2 inhibitor may not be able to suppress pancreatic tumor growth in vivo and its application is further limited by untoward side effects. The present study provides evidence that combined use of celecoxib and 5-LOX inhibitor MK886 markedly suppresses pancreatic tumor cell growth in vitro. Compared to the single inhibitor treatment, dual treatment with celecoxib and MK886 exerted additive antitumor effects in pancreatic tumor cells. We found that MK886 reversed celecoxib-induced increases in 5-LOX gene expression and Erk1/2 activation in pancreatic tumor cells. Moreover, Dual treatment of pancreatic tumor cells with celecoxib and MK886 inhibited the levels of LBT4 receptor BLT1 and vascular endothelial growth factor. Our results imply that combined use of celecoxib and MK886 might be an effective way to treat clinical patients with pancreatic cancer.

Topics: Adenocarcinoma; Arachidonate 5-Lipoxygenase; Celecoxib; Cell Division; Cell Line, Tumor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation; Humans; Indoles; Lipoxygenase Inhibitors; MAP Kinase Signaling System; Molecular Targeted Therapy; Neoplasm Proteins; Pancreatic Neoplasms; Pyrazoles; Receptors, Leukotriene B4; Sulfonamides; Vascular Endothelial Growth Factor A

Pancreatic cancer is the fourth leading cause of cancer death in men and women. Smoking is a documented risk factor for pancreatic cancer, and the risk is increased in smokers who also consume alcohol. Arachidonic acid (AA)-metabolizing enzymes have been implicated in aggressive clinical behavior of pancreatic cancer while mutations in the Ki- ras gene have been associated with prolonged survival and responsiveness to therapy. Using a hamster model of exocrine pancreatic cancer induced by transplacental exposure to ethanol and the tobacco-carcinogen NNK, we have analyzed these tumors for mutations in the ras and p53 genes and tested the modulating effects of the COX inhibitor, ibuprofen, and the FLAP inhibitor, MK886, on the development of pancreatic cancer in this animal model.. Hamsters were given 10% ethanol in the drinking water from the fifth to the last day of their pregnancy and a single dose of NNK on the last day. Starting at 4 weeks of age, groups of offspring were given either the COX inhibitor ibuprofen (infant Motrin oral suspension) or the FLAP-inhibitor MK886 (dissolved in carboxymethylcellulose orally) for life while a group of offspring not receiving any treatment served as positive controls.. None of the induced pancreatic cancers demonstrated mutations in the Ki-, N-, or H- ras or p53 genes. The development of pancreatic cancer in offspring who had been given ibuprofen or MK886 was reduced by 50% or 30%, respectively.. In conjunction with the documented over-expression of COX-2 and LOX in human pancreatic cancer, our findings suggest an important role of the AA-cascade in the genesis of this cancer type and indicate that pharmacological or dietary measures that reduce AA-metabolism may be useful for the prevention and clinical management of pancreatic cancer.

Topics: Adenocarcinoma; Animals; Arachidonic Acid; Cricetinae; Cyclooxygenase Inhibitors; DNA Primers; Ethanol; Female; Genes, p53; Genes, ras; Ibuprofen; Indoles; Lipoxygenase Inhibitors; Male; Maternal-Fetal Exchange; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Pregnancy

Exocrine ductal carcinoma of the pancreas has been associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation, our data show high basal levels of AA release in two human cell lines derived from exocrine ductal pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly stimulated by NNK when cells were maintained in complete medium and this response was inhibited by the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer intervention strategies.

Topics: Adenocarcinoma; Adrenergic beta-Antagonists; Arachidonic Acid; Aspirin; Base Sequence; DNA Primers; Enzyme Inhibitors; Genes, ras; Humans; Indoles; Pancreatic Neoplasms; Propanolamines; Radioligand Assay; Receptors, Adrenergic, beta; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Lung cancer is the leading cause of death in the United States, and it demonstrates a strong etiological association with smoking. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) reproducibly induces pulmonary adenocarcinomas (ACs) in laboratory rodents and is considered an important contributing factor to the high lung cancer burden observed in smokers. It has been shown that the development of NNK-induced ACs in mice is reduced by inhibitors of cyclooxygenase and lipoxygenase and that the growth of human AC cell lines is regulated by beta-adrenergic receptors. On the basis of structural similarities of NNK with classic beta-adrenergic agonists, we tested the hypothesis that NNK stimulates the growth of human AC cells via agonist-binding to beta-adrenergic receptors, resulting in the release of arachidonic acid (AA). In support of this hypothesis, radioreceptor assays with transfected CHO cell lines stably expressing the human beta1- or beta2-adrenergic receptor demonstrated high affinity binding of NNK to each of these receptors. Two human AC cell lines expressed beta1- and beta2-adrenergic receptors by reverse transcription-PCR and responded to NNK with the release of AA and an increase in DNA synthesis. Beta-adrenergic antagonists completely blocked the release of AA and increase in DNA synthesis. The cyclooxygenase inhibitor aspirin and the 5-lipoxygenase inhibitor MK-886 both partially inhibited DNA synthesis in response to NNK. Our findings identify the direct interaction of NNK with beta-adrenergic, AA-dependent pathways as a novel mechanism of action which may significantly contribute to the high cancer-causing potential of this nitrosamine. Moreover, NNK may also contribute to the development of smoking-related nonneoplastic disease via this mechanism.

Topics: Adenocarcinoma; Adrenergic beta-Agonists; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Carcinogens; CHO Cells; Cricetinae; DNA Replication; DNA, Neoplasm; Humans; Indoles; Lipoxygenase Inhibitors; Lung Neoplasms; Mice; Nitrosamines; Radioligand Assay; Receptors, Adrenergic, beta; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Cells, Cultured