4.5 Article

A771726, an anti-inflammatory drug, exerts an anticancer effect and reverses tamoxifen resistance in endocrine-resistant breast cancer cells

期刊

ONCOLOGY REPORTS
卷 32, 期 2, 页码 627-634

出版社

SPANDIDOS PUBL LTD
DOI: 10.3892/or.2014.3249

关键词

A771726; endocrine resistance; tamoxifen; apoptosis; cell cycle; microarray analysis

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资金

  1. National Natural Science Foundation of China [81202549, 81202088, 81302147, 81302145]
  2. National Science and Technology Major Project of the Ministry of Science and Technology of China [2012ZX09301001-007]
  3. Leading Academic Discipline Project of Shanghai Municipal Education Commission [J50208]
  4. Cancer Foundation of China [0901]
  5. Science and Technology Commission of Shanghai Municipality [09411961400]
  6. Shanghai Charity Cancer Research Centre

向作者/读者索取更多资源

A771726, an orally available anti-inflammatory agent, has been approved for the treatment of multiple sclerosis by diminishing entire inflammatory responses through multiple signaling pathways. Recently, a few emerging studies have focused on the potential application of A771726 in cancer therapy, less on the treatment of breast cancer and particularly on overcoming drug resistance in breast cancer. We report here for the first time the cytotoxic activity and drug resistance reversal of A771726 in acquired tamoxifen-resistant breast cancer cell line MCF-7/LCC9. We discovered that A771726 treatment showed antiproliferative activities in MCF-7/LCC9 cells, which were even more sensitive to A771726 than their parental tamoxifen-sensitive cells (MCF-7). A771726 also exerted pro-apoptotic activities and induced cell cycle arrest at the G1 phase. Notably, treatment of A771726 restored the sensitivity of MCF-7/LCC9 cells to tamoxifen. Western blot analysis revealed that A771726 decreased the phosphorylation level of Src, one key driver of tamoxifen resistance. Moreover, in order to comprehensively clarify the mechanisms of A771726 in anti-estrogen-resistant cells, we explored a genome-wide transcriptomic analysis, and showed that A771726 could modulate multiple signaling pathways (e.g. cell cycle, apoptosis, MAPK, metabolism and p53 signaling pathway) and cellular processes (e.g. signal transduction, transcription and cell cycle). Overall, our results indicate that A771726 alone and the combination of A771726 with antiestrogens may be of therapeutic benefit for ER-positive and endocrine-resistant breast cancer.

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