Mebendazole potentiates radiation therapy in triple-negative breast cancer
Menée in vitro et à l'aide d'une xénogreffe de cancer du sein triplement négatif, cette étude met en évidence l'intérêt du mébendazole pour améliorer l'efficacité thérapeutique des rayonnements ionisants
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 BC cells into BC initiating cells (BCICs), that are thought to contribute to disease recurrence. In this study we characterize mebendazole as a drug with potential for preventing radiation-induced reprogramming from occurring and improve the effect of RT in TNBC patients. 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 towards TNBC cells. Mebendazole (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 g-H2AX were 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 radiation therapy in TNBC was evaluated in vitro and in vivo. Results: MBZ efficiently depletes the breast cancer initiating cell pool, as well as prevents the IR-induced conversion of BC cells into therapy resistant BCICs. In addition, MBZ arrests cells in the G2/M phase of the cell cycle arrest and causes double-strand breaks and apoptosis. Mebendazole 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 mebendazole as a combination treatment with radiation therapy in TNBC patients.
https://www.redjournal.org/article/S0360-3016(18)33688-5/fulltext 2018