Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer.
Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer.
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DOI：
10.1016/j.ijrobp.2018.08.046
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Vlashi E
中科院分区：
文献类型：
--
作者：
Zhang L;Bochkur Dratver M;Yazal T;Dong K;Nguyen A;Yu G;Dao A;Bochkur Dratver M;Duhachek-Muggy S;Bhat K;Alli C;Pajonk F;Vlashi E
三阴性乳腺癌（TNBC）缺乏分子靶点，使其成为治疗最具挑战性的乳腺癌之一。放射治疗（RT）是管理乳腺癌的重要治疗方式;然而，我们以前表明RT也可以将一部分存活的乳腺癌细胞重新编程为乳腺癌起始细胞（BCIC），这被认为有助于疾病复发。在这项研究中，我们将甲苯咪唑（MBZ）描述为一种有潜力预防放射诱导重编程发生并改善TNBC患者RT效果的药物。使用高通量筛选来鉴定防止辐射诱导的TNBC细胞转化为具有癌症起始表型的细胞并且对TNBC细胞表现出显著毒性的药物。MBZ是符合这些标准的药物之一。在其他研究中，我们使用BCIC标记物和乳腺球形成试验来研究MBZ对BCIC人群的影响。用碘化丙啶、膜联蛋白-V和γ-H2 AX染色来确定MBZ对细胞周期、凋亡和双链断裂的影响。最后，在体外和体内评估了MBZ增强RT在TNBC中的作用的潜力。MBZ有效地耗尽BCIC库，并防止电离辐射诱导的乳腺癌细胞转化为治疗抗性BCIC。此外，MBZ将细胞阻滞在细胞周期的G2/M期，并导致双链断裂和凋亡。MBZ在体外和体内使TNBC细胞对电离辐射敏感，导致TNBC的人异种移植模型中的肿瘤控制改善。本研究中提供的数据支持MBZ与RT联合治疗TNBC患者的再利用。
The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Radiation therapy (RT) is an important treatment modality for managing breast cancer; however, we previously showed that RT can also reprogram a fraction of the surviving breast cancer cells into breast cancer—initiating cells (BCICs), which are thought to contribute to disease recurrence. In this study, we characterize mebendazole (MBZ) as a drug with potential to prevent the occurrence of radiation-induced reprogramming and improve the effect of RT in patients with TNBC. A high-throughput screen was used to identify drugs that prevented radiation-induced conversion of TNBC cells into cells with a cancer-initiating phenotype and exhibited significant toxicity toward TNBC cells. MBZ was one of the drug hits that fulfilled these criteria. In additional studies, we used BCIC markers and mammosphere-forming assays to investigate the effect of MBZ on the BCIC population. Staining with propidium iodide, annexin-V, and γ-H2AX was used to determine the effect of MBZ on cell cycle, apoptosis, and double-strand breaks. Finally, the potential for MBZ to enhance the effect of RT in TNBC was evaluated in vitro and in vivo. MBZ efficiently depletes the BCIC pool and prevents the ionizing radiation–induced conversion of breast cancer cells into therapy-resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle and causes double-strand breaks and apoptosis. MBZ sensitizes TNBC cells to ionizing radiation in vitro and in vivo, resulting in improved tumor control in a human xenograft model of TNBC. The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC.
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影响因子：
5.8
作者：
LACEY, E;WATSON, TR
通讯作者：
WATSON, TR
FDA 批准的驱虫药氟苯达唑针对乳腺癌干细胞样细胞
影响因子：
--
作者：
Hou ZJ;Luo X;Zhang W;Peng F;Cui B;Wu SJ;Zheng FM;Xu J;Xu LZ;Long ZJ;Wang XT;Li GH;Wan XY;Yang YL;Liu Q
通讯作者：
Liu Q
DOI：
10.1016/0006-291x(80)90349-6
发表时间：
1980-01-01
影响因子：
3.1
作者：
LACLETTE, JP;GUERRA, G;ZETINA, C
通讯作者：
ZETINA, C
影响因子：
5.2
作者：
Cochrane CR;Szczepny A;Watkins DN;Cain JE
通讯作者：
Cain JE
影响因子：
37.3
作者：
Gomez-Casal R;Bhattacharya C;Ganesh N;Bailey L;Basse P;Gibson M;Epperly M;Levina V
通讯作者：
Levina V