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

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Journal of Gastrointestinal Surgery Aims and scope

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.

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Acknowledgments

This work was funded by the Veterans Affairs (VA) Young Investigator Award (C.M.S.) and American Cancer Society grant number RSG-06-267-01-CCE (C.M.S. and M.Y-S.).

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Authors and Affiliations

  1. Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St., Building R3, Rm. 541C, Indianapolis, IN, 46202, USA

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

  2. Department of Biochemistry/Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    C. Max Schmidt

  3. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA

    C. Max Schmidt

  4. Indiana University Cancer Center, Indianapolis, IN, USA

    C. Max Schmidt

  5. Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA

    C. Max Schmidt

  6. University of Kentucky, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Peter A. Crooks

Authors
  1. Bryan K. Holcomb
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  2. Michele T. Yip-Schneider
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  3. Joshua A. Waters
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  4. Joal D. Beane
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  5. Peter A. Crooks
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  6. C. Max Schmidt
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Corresponding authors

Correspondence to Michele T. Yip-Schneider or C. Max Schmidt.

Additional information

Bryan K. Holcomb and Michele T. Yip-Schneider contributed equally to this paper.

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Holcomb, B.K., Yip-Schneider, M.T., Waters, J.A. et al. Dimethylamino Parthenolide Enhances the Inhibitory Effects of Gemcitabine in Human Pancreatic Cancer Cells. J Gastrointest Surg 16, 1333–1340 (2012). https://doi.org/10.1007/s11605-012-1913-7

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  • DOI: https://doi.org/10.1007/s11605-012-1913-7

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