期刊
EBIOMEDICINE
卷 43, 期 -, 页码 201-210出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2019.04.006
关键词
Triple negative breast cancer; Vitamin C; BET inhibitor; Combination therapy; Histone acetylation; HDAC1
资金
- University of Miami Sylvester Comprehensive Cancer Center, Bankhead Coley Cancer Research Program [7BC10]
- Flight Attendant Medical Research Institute
- NIH [R21CA191668, 1R56AG061911]
Background: Bromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care. Methods: The impact of vitamin C on the efficacy of small compounds including BETi was assessed by high-throughput screening. Co-treatment of TNBC by BETi especially JQ1 and vitamin C was evaluated in vitro and in vivo. Findings: High-throughput screening revealed that vitamin C improves the efficacy of a number of structurally-unrelated BETi including JQ1, I-BET762, I-BET151, and CPI-203 in treating TNBC cells. The synergy between BETi and vitamin C is due to suppressed histone acetylation (H3ac and H4ac), which is in turn caused by upregulated histone deacetylase 1 (HDAC1) expression upon vitamin C addition. Treatment with JQ1 at lower doses together with vitamin C induces apoptosis and inhibits the clonogenic ability of cultured TNBC cells. Oral vitamin C supplementation renders a sub-therapeutic dose of JQ1 able to inhibit human TNBC xenograft growth and metastasis in mice. Interpretation: Vitamin C expands the therapeutic window of BETi by sensitizing TNBC to BETi. Using vitamin C as a co-treatment, lower doses of BETi could be used to achieve an increased therapeutic index in patients, which will translate to a reduced side effect profile. (C) 2019 The Authors. Published by Elsevier B.V.
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