Anticancer Effect of Benzimidazole Derivatives, Especially Mebendazole, on Triple-Negative Breast Cancer (TNBC) and Radiotherapy-Resistant TNBC In Vivo and In Vitro

Abstract

In this study, we aimed to evaluate the anticancer effect of benzimidazole derivatives on triple-negative breast cancer (TNBC) and investigate its underlying mechanism of action. Several types of cancer and normal breast cells including MDA-MB-231, radiotherapy-resistant (RT-R) MDA-MB-231, and allograft mice were treated with six benzimidazole derivatives including mebendazole (MBZ). Cells were analyzed for viability, colony formation, scratch wound healing, Matrigel invasion, cell cycle, tubulin polymerization, and protein expression by using Western blotting. In mice, liver and kidney toxicity, changes in body weight and tumor volume, and incidence of lung metastasis were analyzed. Our study showed that MBZ significantly induced DNA damage, cell cycle arrest, and downregulation of cancer stem cell markers CD44 and OCT3/4, and cancer progression-related ESM-1 protein expression in TNBC and RT-R-TNBC cells. In conclusion, MBZ has the potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.

Mebendazole Increases Anticancer Activity of Radiotherapy in Radiotherapy-Resistant Triple-Negative Breast Cancer Cells by Enhancing Natural Killer Cell-Mediated Cytotoxicity

“…In our previous study, MBZ hardly affected cell viability at doses of 0.01, 0.1, 0.5, 1, 2, 5, and 10 μM for 24 h in MDA-MB-231 cells and RT-R-MDA-MB-231 cells. However, when incubated for 72 h after 10 μM of MBZ administration, cell viability was slightly decreased by approximately 35–50% compared to the control [ 9 ]. Based on this result, 10 mg/kg of MBZ was tested for in vivo study and showed no hepatic damage, kidney toxicity, or body weight loss, but exhibited a significant decrease in tumor volume and lung metastasis.…”

“…In the field of oncology, research is being conducted to supplement existing treatments for various cancers by harnessing the anticancer effect of anthelmintics [ 8 ]. In a previous study, we found that MBZ alone had anticancer effects in RT-resistant TNBC by inducing apoptosis and cell cycle arrest, suppressing the expression of cancer stem cell markers (CD44 and OCT3/4), and inhibiting cancer progression-related ESM-1 proteins [ 9 ]. Herein, we found that the coadministration of MBZ and RT increased the anticancer effect in RT-resistant TNBC compared to MBZ or RT individual regimens.…”

“…In this study, the enhanced anticancer effect of the combination regimen was associated with increased cyclin B1 expression. In a previous study, MBZ induced cell cycle arrest in the G2/M phase by increasing cyclin B1 expression and inhibiting tubulin polymerization [ 9 ]. From this result, it can be inferred that MBZ + RT can promote cell cycle arrest in the G2/M phase through an increase in cyclin B1.…”

“…Consequently, these agents displayed anticancer effects in several cell lines and animal studies without causing serious side effects [ 7 , 8 ]. Further, we found that mebendazole (MBZ), a benzimidazole derivative, exhibited the most effective anticancer effects in TNBC through inducing DNA damage, cell cycle arrest, and downregulating cancer stem cell markers CD44 and OCT3/4 and cancer progression-related ESM-1 protein expression [ 9 ]. Moreover, other studies that researched on cancer stem cells or cells resistant to approved treatment options reported that MBZ monotherapy has anticancer effects as a repurposed drug, and it also stimulated anti-tumor immune responses in synergy with ionizing radiation and various chemotherapeutic agents [ 10 , 11 , 12 ].…”

New spectrophotometric method for determination of mebendazole by oxidative coupling reaction

“…MBL shows direct cytotoxic action, yet in addition synergizes with radiation and different chemotherapeutic specialists, and animates the counter cancer resistant reaction in the body, Studies have shown that MBL fundamentally makes harm the DNA of a disease cell, hence halting its development and it its spread to decrease. (7,8) .…”