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Deguelin, an Akt Inhibitor, Down-Regulates NF-κB Signaling and Induces Apoptosis in Colon Cancer Cells and Inhibits Tumor Growth in Mice

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Abstract

Background

Deguelin, a naturally occurring rotenoid, is known to be an Akt inhibitor and to have an anti-tumor effect on several cancers.

Aims

This study was performed to elucidate the effect of deguelin on apoptotic pathways related to NF-κB signaling in colon cancer cells and on the anti-tumor effect in colon cancer xenograft mice.

Methods

We studied COLO 205 and HCT116 cells in the presence or absence of deguelin. NF-κB signaling was examined by real-time RT-PCR for interleukin (IL)-8, by Western blotting for IκB phosphorylation/degradation, and by the electrophoretic mobility shift assay. Cell death was determined by the MTT assay, and apoptosis by Annexin V-FITC staining and caspase-3 activity. We also assessed the expression of antiapoptotic and proapoptotic factors by use of RT-PCR. In colon cancer xenograft mice, we evaluated the effect of deguelin on inoculated tumor growth, and apoptotic index was measured by the in vivo TUNEL assay.

Results

Deguelin significantly inhibited IL-8 gene expression, IκB phosphorylation/degradation, and DNA binding activity of NF-κB in colon cancer cells. Deguelin induced cell death and apoptosis in colon cancer cells in a dose and time-dependent manner. Deguelin down-regulated expression of NF-κB-mediated antiapoptotic factors such as cFLIP, Bcl-2, and Bcl-XL. In the colon cancer xenograft model, the volume of the tumor treated with deguelin was significantly lower than that of the control, and the apoptotic index for deguelin-treated mice was much higher.

Conclusion

Deguelin might be a potential therapeutic agent for treatment of colorectal cancer.

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Acknowledgments

This study was supported in part by grant no. 03-2009-0060 from the SNUH Research Fund. The authors thank Chi-Yeon Lim, Ph.D., for her assistance with statistics.

Conflict of interest

The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Internal Medicine, Dongguk University Ilsan Hospital, Seoul, Korea

    Hyoun Woo Kang

  2. Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Korea

    Jung Mogg Kim

  3. Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, South Korea

    Mi Yeon Cha, Hyun Chae Jung, In Sung Song & Joo Sung Kim

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  1. Hyoun Woo Kang
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  2. Jung Mogg Kim
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Correspondence to Joo Sung Kim.

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Kang, H.W., Kim, J.M., Cha, M.Y. et al. Deguelin, an Akt Inhibitor, Down-Regulates NF-κB Signaling and Induces Apoptosis in Colon Cancer Cells and Inhibits Tumor Growth in Mice. Dig Dis Sci 57, 2873–2882 (2012). https://doi.org/10.1007/s10620-012-2237-x

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  • DOI: https://doi.org/10.1007/s10620-012-2237-x

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