Dimethylamino Parthenolide Enhances the Inhibitory Effects of Gemcitabine in Human Pancreatic Cancer Cells

Bryan K. Holcomb, Michele T. Yip-Schneider, Joshua A. Waters, Joal D. Beane, Peter A. Crooks, C. Max Schmidt

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Introduction: Gemcitabine is standard treatment for pancreatic cancer but has limited clinical benefit due to chemoresistance. Nuclear factor-kappaB (NF-κB) can promote chemoresistance and is therefore an attractive therapeutic target. We hypothesize that NF-κB suppression with the novel, orally bioavailable inhibitor dimethylamino parthenolide (DMAPT) will sensitize pancreatic cancer cells to gemcitabine. Methods: BxPC-3, PANC-1, and MIA PaCa-2 human pancreatic cancer cell lines were treated with gemcitabine and/or DMAPT. Effects on the NF-κB pathway were determined by electrophoretic mobility shift assay, ELISA, or Western blot. Proliferation and apoptosis were measured by cell counts and ELISA, respectively. The effect of gemcitabine in vivo was determined using a MIA PaCa-2 heterotopic xenograft model. Results: Gemcitabine induced NF-κB activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-κB inhibitor IκBα in BxPC-3 and PANC-1 cells. DMAPT prevented the gemcitabine-induced activation of NF-κB. The combination of DMAPT/gemcitabine inhibited pancreatic cancer cell growth more than either agent alone. Gemcitabine also induced intratumoral NF-κB activity in vivo. Conclusions: DMAPT enhanced the anti-proliferative effects of gemcitabine in association with NF-κB suppression in pancreatic cancer cells in vitro. Furthermore, gemcitabine induced NF-κB activity in vivo, thus supporting the evaluation of NF-κB-targeted agents to complement gemcitabine-based therapies.

Original languageEnglish (US)
Pages (from-to)1333-1340
Number of pages8
JournalJournal of Gastrointestinal Surgery
Volume16
Issue number7
DOIs
StatePublished - Jul 1 2012

Keywords

  • DMAPT
  • NF-κB
  • Pancreatic cancer
  • Parthenolide and gemcitabine

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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