High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors.
High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors.
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DOI：
10.4161/cc.26063
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Zacksenhaus E
中科院分区：
文献类型：
--
作者：
Robinson TJ;Pai M;Liu JC;Vizeacoumar F;Sun T;Egan SE;Datti A;Huang J;Zacksenhaus E
三阴性乳腺癌（TNBC）是一种侵袭性亚型，放射和化疗是唯一的选择。在这里，我们描述了双硫仑的鉴定，双硫仑是FDA批准的用于治疗酒精中毒的药物，以及相关化合物福美双，作为针对多种TNBC细胞系的3185种化合物的高通量筛选后最有效的生长抑制剂。双硫仑的平均IC 50约为300 nM。药物亲和反应靶点稳定性（DARTS）分析鉴定了含IQ基序的因子IQGAP 1和MYH 9作为双硫仑的直接结合靶点。事实上，这些因子的敲除降低了细胞生长，尽管没有完全消除。用常用于治疗TNBC的4种不同药物的组合治疗揭示双硫仑与多柔比星最有效地协同作用以抑制TNBC细胞的细胞生长。双硫仑和多柔比星协同诱导细胞死亡以及细胞衰老，并靶向ESA+/CD 24-/低/CD 44+癌症干细胞群。我们的研究结果表明，双硫仑可能被重新用于与多柔比星联合治疗TNBC。
Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC50 for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA+/CD24-/low/CD44+ cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin.
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影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
50.3
作者：
Jackson JG;Pant V;Li Q;Chang LL;Quintás-Cardama A;Garza D;Tavana O;Yang P;Manshouri T;Li Y;El-Naggar AK;Lozano G
通讯作者：
Lozano G
影响因子：
8
作者：
Hui, L.;Zheng, Y.;Foster, D. A.
通讯作者：
Foster, D. A.
影响因子：
6.4
作者：
Hayashi, Hiroyuki;Nabeshima, Kazuki;Iwasaki, Hiroshi
通讯作者：
Iwasaki, Hiroshi
DOI：
10.1111/j.1600-0773.1991.tb01215.x
发表时间：
1991-03-01
期刊：
PHARMACOLOGY & TOXICOLOGY
影响因子：
--
作者：
CHRISTENSEN, JK;MOLLER, IW;JOHANSSON, B
通讯作者：
JOHANSSON, B