Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
Int J Radiat Oncol Biol Phys. 2019 Jan 1;103(1):195-207. doi: 10.1016/j.ijrobp.2018.08.046. Epub 2018 Sep 7.
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.
三阴性乳腺癌（TNBC）缺乏分子靶点，使其成为最难治疗的乳腺癌之一。放射治疗（RT）是治疗乳腺癌的重要手段；然而，我们之前的研究表明，RT 还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），这些细胞被认为是导致疾病复发的原因之一。在这项研究中，我们将苯并咪唑（MBZ）鉴定为一种具有预防辐射诱导重编程和提高 TNBC 患者 RT 效果潜力的药物。
我们使用高通量筛选来鉴定可预防 TNBC 细胞向具有起始癌症表型的细胞转化且对 TNBC 细胞具有显著毒性的药物。MBZ 是符合这些标准的药物之一。在进一步的研究中，我们使用 BCIC 标记物和乳腺球体形成测定来研究 MBZ 对 BCIC 群体的影响。使用碘化丙啶、膜联蛋白-V 和 γ-H2AX 染色来确定 MBZ 对细胞周期、细胞凋亡和双链断裂的影响。最后，评估了 MBZ 在体外和体内增强 TNBC 放疗效果的潜力。
MBZ 有效地耗尽了 BCIC 池，并防止电离辐射诱导的乳腺癌细胞向耐药性 BCIC 的转化。此外，MBZ 将细胞阻滞在细胞周期的 G2/M 期，并导致双链断裂和细胞凋亡。MBZ 在体外和体内使 TNBC 细胞对电离辐射敏感，从而改善了 TNBC 人异种移植模型中的肿瘤控制。
本研究中的数据支持将 MBZ 重新用于与 RT 联合治疗 TNBC 患者。
