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Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway

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Abstract

The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone-associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL.

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Acknowledgments

This work was supported by grants from Chinese Universities Scientific Fund (2009-2-11), National Natural Science Foundation of China (NSFC, 31071533, 30972172). We thank Prof. Carine Michiels for generously providing the pCMV-HA-Mcl-1 plasmid and Prof. Junxuan Lu for providing valuable comments and writing assistance.

Conflict of interest

The authors have no conflicts of interest to disclosure.

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Authors and Affiliations

  1. Division of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No 17 Qinghua East Road, Haidian District, Beijing, 100083, China

    Yinhui Dong, Shutao Yin, Jinghua Li & Hongbo Hu

  2. The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA

    Cheng Jiang

  3. The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, No 38 Xueyuan Rd., Haidian District, Beijing, 100191, China

    Min Ye

Authors
  1. Yinhui Dong
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  2. Shutao Yin
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  3. Jinghua Li
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  4. Cheng Jiang
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  5. Min Ye
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  6. Hongbo Hu
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Correspondence to Min Ye or Hongbo Hu.

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Dong, Y., Yin, S., Li, J. et al. Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway. Apoptosis 16, 394–403 (2011). https://doi.org/10.1007/s10495-011-0573-5

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