A structurally optimized celecoxib derivative inhibits human pancreatic cancer cell growth

Junan Li, Jiuxiang Zhu, W. Scott Melvin, Tanios S. Bekaii-Saab, Ching Shih Chen, Peter Muscarella

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Deregulation of the phosphatidylinositol 3-kinase (PI-3K)/PDK-l/Akt signaling cascade is associated with pancreatic cancer tumor invasion, angiogenesis, and tumor progression. As such, it has been postulated that PDK-1/Akt signaling inhibitors may hold promise as novel therapeutic agents for pancreatic cancer. Disadvantages of currently available Akt inhibitors include tumor resistance, poor specificity, potential toxicity, and poor bioavailability. Previous studies have demonstrated that OSU-03012, a celecoxib derivative, specifically inhibits PDK-1 mediated phosphorylation of Akt with IC50 values in the low μM range. Human pancreatic cancer cell lines AsPC-1, BxPC-3, Mia-PaCa 2, and PANC-1 were cultured in media containing varying concentrations of OSU-03012, 5-fluorouracil (5-FU), and gemcitabine, and changes in Akt phosphorylation and cell viability were evaluated using western blotting and a 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay, respectively. Treatment with OSU-03012 resulted in decreased PDK-1-mediated Akt phosphorylation and cell growth inhibition for all cell lines with IC50 values ranging between 1.0 and 2.5 μM. Resistance to 5-FU and gemcitabine was observed in cell lines AsPC-1 and BxPC-3. Further analyses indicate that OSU-03012 induces both proapoptotic and antiproliferative effects in these cells. Taken together, these data suggest that OSU-03012 has potential value as a novel therapy for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)207-214
Number of pages8
JournalJournal of Gastrointestinal Surgery
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2006

Keywords

  • Akt signaling
  • Celecoxib
  • PDK-1 specific inhibitor
  • Pancreatic cancer

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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