Metastatic
breast cancer (mBC) is responsible for >90% of
breast cancer-related deaths. Microtubule-targeting agents (MTAs) are the front-line treatment for mBC. However, the effectiveness of MTAs is frequently limited by the primary or acquired resistance. Furthermore, recurrent mBC derived from
cancer cells that survived
MTA treatment are typically more chemoresistant. The overall response rates for the second- and third-line MTAs in mBC patients previously treated with MTAs are 12-35%. Thus, there is an ongoing search for novel MTAs with a distinct mode of action that can circumvent chemoresistance mechanisms. Our results show that methyl N-(6-benzoyl-1H-benzimidazol-2-yl)carbamate (BCar), a microtubule-disrupting
anthelmintic that binds to the
colchicine binding site separate from the binding sites of clinically used MTAs, has the potential to treat
MTA-resistant mBC. We have comprehensively evaluated the cellular effects of BCar in a panel of human
breast cancer (BC) cell lines and normal breast cells. BCar effects on the clonogenic survival, cell cycle, apoptosis, autophagy, senescence, and mitotic catastrophe were measured. Approximately 25% of BCs harbor mutant p53. For this reason, the p53 status was included as a variable. The results show that BC cells are >10x more sensitive to BCar than normal mammary epithelial cells (HME). p53-mutant BC cells are significantly more sensitive to BCar treatment than p53 wild-type BC cells. Furthermore, BCar appears to kill BC cells primarily via either p53-dependent apoptosis or p53-independent mitotic catastrophe. When compared to
docetaxel and
vincristine, two clinical MTAs, BCar is fairly innocuous in HME cells, providing a much wider therapeutic window than
docetaxel and
vincristine. Together, the results strongly support the notion that BCar-based
therapeutics may serve as a new line of MTAs for mBC treatment.