Enhancing antitumor effects in pancreatic cancer cells by combined use of COX-2 and 5-LOX inhibitors

Biomed Pharmacother. 2011 Oct;65(7):486-90. doi: 10.1016/j.biopha.2011.06.009. Epub 2011 Aug 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Arachidonate 5-Lipoxygenase / physiology
  • Celecoxib
  • Cell Division / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / enzymology
  • Cyclooxygenase 2 / physiology
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Humans
  • Indoles / administration & dosage
  • Indoles / pharmacology*
  • Lipoxygenase Inhibitors / administration & dosage
  • Lipoxygenase Inhibitors / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Molecular Targeted Therapy
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / pathology*
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology*
  • Receptors, Leukotriene B4 / biosynthesis
  • Receptors, Leukotriene B4 / genetics
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Cyclooxygenase 2 Inhibitors
  • Indoles
  • LTB4R protein, human
  • Lipoxygenase Inhibitors
  • Neoplasm Proteins
  • Pyrazoles
  • Receptors, Leukotriene B4
  • Sulfonamides
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • MK-886
  • Arachidonate 5-Lipoxygenase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Celecoxib