Efficacy And Mechanism Of Benzimidazole Derivative Against Breast Cancer Cells In Vitro And In Vivo

Aberrant expression or function of epidermal growth factor receptor(EGFR) or the closely related human epidermal growth factor receptor 2(HER2) can promote cell proliferation andsurvival, thereby contributing to tumorigenesis. Specific antibodies andlow molecularweight tyrosine kinase inhibitors of both proteins are currently in clinicaltrials for cancer treatment.Benzimidazole derivatives possess diversebiological activities, including antimicrobial, antiviral, anti-inflammatory and anticarcinogenic activity.One of these analogs, a novel 2-aryl benzimidazolederivative(5a),which was found toinduce apoptosis in a human hepatocellular carcinoma cell.However the anti-cancer mechanism of 5atoward breast cancer is largely unknown. Here, we demonstrate that5 apotently inhibited both EGFR and HER2 activity by reducing EGFR and HER2 tyrosinephosphorylation andpreventingdownstreamactivationofPI3K/Akt and MAPK/Erkpathwaysin vitroandin vivo.We also show that 5a inhibited the phosphorylation of Forkhead box protein O(FOXO) and promoted FOXO translocation from the cytoplasm into the nucleus, resulting in G1 phase cell cycle arrest and apoptosis.Moreover, 5apotently induced apoptosis via the c-Jun N-terminal kinase(JNK)-mediated death receptor 5(DR5) upregulation inbreast cancer cells.The antitumor activity of 5awas consistentwith additional results demonstrating that 5a significantly reduced tumor volumein nude miceinvivo.Analysis from the primary breast cancer cell lines with HER2 overexpression, further confirmed that 5a significantlyinhibitedAkt Ser473 and Bad Ser136 phosphorylation and reduced cyclin D3 expression. On the basis of ourfindings, further development of this 2-aryl benzimidazole derivative, anew class ofmulti-targetanticancer agents, is warranted and represents a novel strategy for improving breast cancer treatment.