Abstract P3-07-01: Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe

Abstract

Abstract Metastatic breast cancer (mBC) is still an incurable disease and is responsible for the majority of breast cancer-related death, despite tremendous efforts spent on developing better regimens for mBC. Microtubule-targeting chemotherapy agents (MTAs) have been on the front lines of treating mBC. However, many of these drugs become ineffective following treatment, as a consequence of either primary or acquired resistance, which leads to refractory disease. Furthermore, failures of the first-line MTA treatment will negatively affect the effectiveness of the second- and third-line agents in the patients, as the overall response rates of the subsequent treatments are in a range of only ~12% to 35%. Thus, there is an urgent need for alternative MTAs that are significantly different in biological characteristics from those currently used MTAs for mBC therapy. For this purpose, we investigated Mebendazole (methyl 5-benzoyl-2-benzimidazole-carbamate (MEB), which binds different sites on the α/β-tubulin remote from the binding sites of other MTAs, for its potential against mBC cells. MEB has much lower in vivo toxicity than the other MTAs used to treat mBC and it can be orally administrated. We explored MEB for its effectiveness in anti-mBC cells with a panel of human breast normal and mBC cell lines. The data from clonogenic survival studies indicate that MEB delivers < 10-fold greater cytotoxicity toward mBC cells compared to normal mammary epithelial (HME) or benign breast tumor cells. Furthermore, the cytotoxicity in detected in mBC cells was attributed to the induction of mitotic catastrophe, as demonstrated by the increased mitotic cell population (cells with 4N-DNA content and Histon-H3-Ser10 phosphorylation) and concurrent nuclear fragmentation. In contrast, under the same dose range, MEB did not cause mitotic catastrophe in HME cells. In addition, our data also show that MEB is much more efficient in killing p53-deficient mBC cells than p53-proficient mBC cells for the same reason, induction of mitotic catastrophe, which suggest the protective function of p53 against MEB-induced mitotic catastrophe. Collectively, our data support a great potential for MEB as an innovative regimen for improving mBC treatment. Citation Format: Ying Yan, Janina Baranowska-Kortylewicz, Brendan Graff. Mebendazole displays selective anti-breast cancer cytotoxicity via the induction of mitotic catastrophe [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-01.