Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer
| Autor: | Kruttika Bhat, Michael Bochkur Dratver, Amy Dao, Milana Bochkur Dratver, Le Zhang, Claudia Alli, Kevin Dong, Garrett Yu, Erina Vlashi, Andrea Nguyen, Frank Pajonk, Taha Yazal, Sara Duhachek-Muggy |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
medicine.medical_treatment Apoptosis Triple Negative Breast Neoplasms 030218 nuclear medicine & medical imaging chemistry.chemical_compound Mice Double-Stranded 0302 clinical medicine Stem Cell Research - Nonembryonic - Human Medicine DNA Breaks Double-Stranded Triple-negative breast cancer Cancer education.field_of_study Radiation Tumor Cell cycle Other Physical Sciences Mebendazole Oncology 030220 oncology & carcinogenesis Female Reprogramming Biotechnology Population Clinical Sciences Oncology and Carcinogenesis Article Cell Line 03 medical and health sciences Breast cancer Cell Line Tumor Breast Cancer Genetics Animals Humans Radiology Nuclear Medicine and imaging Propidium iodide Oncology & Carcinogenesis education business.industry Prevention DNA Breaks Cell Dedifferentiation medicine.disease Stem Cell Research High-Throughput Screening Assays Radiation therapy chemistry Cancer research business |
| Zdroj: | International journal of radiation oncology, biology, physics, vol 103, iss 1 |
| Popis: | Purpose 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. Methods and Materials 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. Results 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. Conclusions The data presented in this study support the repurposing of MBZ as a combination treatment with RT in patients with TNBC. |
| Databáze: | OpenAIRE |
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