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BAY 11-7082, a nuclear factor-κB inhibitor, induces apoptosis and S phase arrest in gastric cancer cells

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Abstract

Background

Inhibitors of nuclear factor (NF)-κB pathway have shown potential anti-tumor activities. However, it is not fully elucidated in gastric cancer.

Methods

Firstly, we screened the inhibitory effect of pharmacologic NF-κB inhibitors on cell viability of human gastric cancer cells via CCK-8 assay. Next, cell apoptosis, cell cycle distribution, and mitochondrial membrane potential after BAY 11-7082 treatment were detected by annexin V staining, propidium iodide staining, TUNEL, and JC-1 assays in human gastric cancer HGC-27 cells. Expression of regulatory factors for apoptosis and cell cycle were measured by western blot. Finally, human gastric cancer xenograft model was established to verify the anti-tumor effects of BAY 11-7082 in vivo. Cellular apoptosis and growth inhibition in subcutaneous tumor section were detected by TUNEL and immunohistochemistry assays.

Results

BAY 11-7082 exhibited rapid and potent anti-tumor effects on gastric cancer cells in vitro within a panel of NF-κB inhibitors. BAY 11-7082 induced rapid apoptosis in HGC-27 cells through activating the mitochondrial pathway, as well as down-regulation of Bcl-2 and up-regulation of Bax. BAY 11-7082 also induced S phase arrest through suppressing Cyclin A and CDK-2 expression. Xenograft model confirmed the anti-tumor effects of BAY 11-7082 on apoptosis induction and growth inhibition in vivo.

Conclusions

Our results demonstrated that BAY 11-7082 presented the most rapid and potent anti-tumor effects within a panel of NF-κB inhibitors, and could induce cellular apoptosis and block cell cycle progression both in vitro and in vivo, thus providing basis for clinical application of BAY 11-7082 in gastric cancer cases.

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Acknowledgments

This work was supported by grants from the National Basic Research Program of China 973 Program (Grant Nos. 2012CB822104, 2010CB912104), the State Key Project Specialized for Infectious Diseases of China (Grant Nos. 2012ZX10002-008, 2012ZX10002-012), the National High-Tech R&D 863 Program (Grant No. 2012AA020203), the National Natural Science Fund (Grant Nos. 30930025, 31010103906, 31170766, 31100629, 31270863), and the Key Project of Science and Technology Commission of Shanghai Municipality (Grant Nos. 09DZ1950101, 11411951000).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    Ling Chen, Xuefei Wang, Lingqiang Min, Zhenbin Shen, Yihong Sun & Xinyu Qin

  2. Gene Research Center, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

    Yuanyuan Ruan

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  1. Ling Chen
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  2. Yuanyuan Ruan
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  3. Xuefei Wang
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  4. Lingqiang Min
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Correspondence to Yihong Sun or Xinyu Qin.

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L. Chen, Y. Ruan and X. Wang contributed equally to this work.

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Chen, L., Ruan, Y., Wang, X. et al. BAY 11-7082, a nuclear factor-κB inhibitor, induces apoptosis and S phase arrest in gastric cancer cells. J Gastroenterol 49, 864–874 (2014). https://doi.org/10.1007/s00535-013-0848-4

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