期刊
LIFE SCIENCES
卷 213, 期 -, 页码 149-157出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2018.10.034
关键词
Autophagy; Histone deacetylase 6; Phosphatase and tensin homolog; Sulforaphane; Triple negative breast cancer
资金
- National Natural Science Foundation of China [81772833]
- Natural Science Foundation of Hubei province [2017CFB556]
- Open Foundation of Key Laboratory of Occurrence and Intervention of Rheumatic Diseases of Hubei Province [OIR13012A, OIR13003A]
- Scientific research and developing project of Yichang [A17-301-23]
Aims: To study the underlying mechanisms of sulforaphane, a natural histone deacetylase (HDAC) inhibitor, in inhibiting triple negative breast cancer cells growth and the therapeutic effects of combination of sulforaphane and doxorubicin in TNBC treatment. Materials and methods: The antineoplastic activity of sulforaphane was evaluated in MDA-MB-231, BT549 and MDA-MB-468 cells with MTT assay. Cell apoptosis was detected with Annexin V/PI double staining by Flow cytometry. Cell autophagy was detected with fluorescence microscope. The effects of Sulforaphane and Doxorubicin combination treatments on cells growth were determined with Chou-Talalay median effect/combination index (CI) model. mRNA and protein expression of genes were assayed respectively with real-time PCR and Western bloting. Protein-protein interaction was detected with co-immunoprecipation. Gene knock-down was performed with small interfere RNA. In vivo assay of combinational treatment with sulforaphane and doxorubicin was investigated in athymic nude mice bearing MDA-MB-231 xenografts. Key findings: Results showed that sulforaphane inhibited cell growth and induced autophagy in MDA-MB-231, BT549 and MDA-MB-468 cells. Further study demonstrated that sulforaphane induced autophagy by down-regulating expression of HDAC6, which resulted in increased membrane translocation and acetylation modification of phosphatase and tensin homolog (PTEN). Sulforaphane and doxorubicin combination exhibited a synergistic inhibition on TNBC cells growth. In nude mice, the combination of sulforaphane and doxorubicin displayed a greater inhibitory effect on MDA-MB-231 xenografts growth as compared to either treatment alone. Significance: Our study suggested that induction of autophagy by targeting HDAC6 in combination with chemotherapeutic reagent may provide a novel strategy for TNBC therapy.
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