Vitamin C supplementation expands the therapeutic window of BETi for triple negative breast cancer
Vitamin C supplementation expands the therapeutic window of BETi for triple negative breast cancer
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DOI：
10.1016/j.ebiom.2019.04.006
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发表时间：
2019-05-01
期刊：
影响因子：
11.1
通讯作者：
Wang, Gaofeng
中科院分区：
文献类型：
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作者：
Mustafi, Sushmita;Camarena, Vladimir;Wang, Gaofeng
背景：溴域和外端抑制剂（BETi）已显示出治疗侵袭性三阴性乳腺癌（TNBC）的疗效。然而，BETi的治疗窗口很窄，在有效剂量下表现出严重的毒性。因此，限制了它们在患者护理中的临床应用。方法：采用高通量筛选法评价维生素C对BETi等小化合物药效的影响。体外和体内评价了BETi特别是JQ1和维生素C对TNBC的联合治疗作用。结果：高通量筛选显示，维生素C提高了一些结构无关的BETi，包括JQ1， I-BET762， I-BET151和ppi -203治疗TNBC细胞的功效。BETi和维生素C之间的协同作用是由于组蛋白乙酰化（H3ac和H4ac）受到抑制，而这又由添加维生素C后组蛋白去乙酰化酶1 （HDAC1）表达上调引起。低剂量JQ1联合维生素C可诱导TNBC细胞凋亡并抑制其克隆生成能力。口服维生素C补充使亚治疗剂量的JQ1能够抑制小鼠TNBC异种移植物的生长和转移。解释：维生素C通过使TNBC对BETi增敏，扩大了BETi的治疗窗口。使用维生素C作为联合治疗，较低剂量的BETi可以提高患者的治疗指数，这将转化为减少副作用。(C) 2019作者。Elsevier B.V.出版
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.