Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine

Authors

  • Hong-Quan Duong,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    2. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
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    • These authors contributed equally to this work.
  • Young Bin Hong,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    Current affiliation:
    1. Department of Neurology, School of Medicine, Ewha Womans University, Seoul, Korea
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    • These authors contributed equally to this work.
  • Jung Soon Kim,

    1. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
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  • Hee-Seok Lee,

    1. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
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  • Yong Weon Yi,

    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    2. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
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  • Yeon Jeong Kim,

    1. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
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  • Antai Wang,

    1. Department of Biostatistics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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  • Wenjing Zhao,

    1. Department of Biostatistics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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  • Chi Heum Cho,

    1. Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu, Korea
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  • Yeon-Sun Seong,

    Corresponding author
    1. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
    • Correspondence to: Dr. Insoo BAE, Department of Oncology and Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.

      Tel.: +1 202 687 5267

      Fax: +1 202 687 2847

      E-mail: ib42@georgetown.edu

      Dr. Yeon-Sun SEONG, WCU Research Center of Nanobiomedical Science, Dankook University, Cheonan 330-714, Korea.

      Tel.: +82 415503875

      Fax: +82 415501149

      E-mail: seongys@chol.com

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  • Insoo Bae

    Corresponding author
    1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    2. WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea
    3. Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
    • Correspondence to: Dr. Insoo BAE, Department of Oncology and Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.

      Tel.: +1 202 687 5267

      Fax: +1 202 687 2847

      E-mail: ib42@georgetown.edu

      Dr. Yeon-Sun SEONG, WCU Research Center of Nanobiomedical Science, Dankook University, Cheonan 330-714, Korea.

      Tel.: +82 415503875

      Fax: +82 415501149

      E-mail: seongys@chol.com

    Search for more papers by this author

Abstract

Checkpoint kinase 2 (CHK2) plays pivotal function as an effector of cell cycle checkpoint arrest following DNA damage. Recently, we found that co-treatment of NSC109555 (a potent and selective CHK2 inhibitor) potentiated the cytotoxic effect of gemcitabine (GEM) in pancreatic cancer MIA PaCa-2 cells. Here, we further examined whether NSC109555 could enhance the antitumour effect of GEM in pancreatic adenocarcinoma cell lines. In this study, the combination treatment of NSC109555 plus GEM demonstrated strong synergistic antitumour effect in four pancreatic cancer cells (MIA PaCa-2, CFPAC-1, Panc-1 and BxPC-3). In addition, the GEM/NSC109555 combination significantly increased the level of intracellular reactive oxygen species (ROS), accompanied by induction of apoptotic cell death. Inhibition of ROS generation by N-acetyl cysteine (NAC) significantly reversed the effect of GEM/NSC109555 in apoptosis and cytotoxicity. Furthermore, genetic knockdown of CHK2 by siRNA enhanced GEM-induced apoptotic cell death. These findings suggest that inhibition of CHK2 would be a beneficial therapeutic approach for pancreatic cancer therapy in clinical treatment.

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