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Bafilomycin C1 induces G0/G1 cell-cycle arrest and mitochondrial-mediated apoptosis in human hepatocellular cancer SMMC7721 cells

The Journal of Antibioticsvolume 71pages808817 (2018) | Download Citation

Abstract

Bafilomycin C1, which was isolated from Streptomyces albolongus in our previous work, exhibited strong cytotoxicity against several cancer cell lines. This study aimed to evaluate its antitumor effect on human hepatocellular cancer SMMC7721 cells and the underlying mechanism in vitro and in vivo. MTT assay revealed that bafilomycin C1 retarded SMMC7721 cell growth and proliferation. Western blot and real-time qPCR analysis revealed that bafilomycin C1 caused partial G0/G1 phase cell-cycle arrest, downregulated the expression of cyclin D3, cyclin E1, CDK2, CDK4, and CDK6 and upregulated the expression of p21. Moreover, bafilomycin C1 caused mitochondrial membrane dysfunction through oxidative stress. Furthermore, bafilomycin C1 decreased the expression of Bcl-2; increased the expression of Bax, p53, and P-p53; and increased cleavage of caspase-9 and caspase-3, thereby inducing the intrinsic caspase-dependent apoptotic pathway. In vivo experiments in mice suggested that bafilomycin C1 suppressed tumor growth with few side effects. Cell-cycle arrest and induced apoptosis in tumor tissues in a mouse model treated with bafilomycin C1 were demonstrated by histological analyses, western blot and TUNEL. These findings indicate that bafilomycin C1 may be a promising candidate for hepatic cellular cancer therapy.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (Grant No. 81573327).

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Affiliations

  1. Institute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, 110819, Shenyang, P. R. China

    • Xiaoxiao Gao
    • , Li Han
    • , Nan Ding
    • , Yu Mu
    • , Peipei Guan
    • , Caijuan Hu
    •  & Xueshi Huang

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The authors declare that they have no conflict of interest.

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Correspondence to Li Han or Xueshi Huang.

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DOI

https://doi.org/10.1038/s41429-018-0066-7