Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells

Abstract

Cancer stem-like cell (CS-like cell) is considered to be responsible for recurrence and drug resistance events in breast cancer, which makes it a potential target for novel cancer therapeutic strategy. The FDA approved flubendazole, has been widely used in the treatment of intestinal parasites. Here, we demonstrated a novel effect of flubendazole on breast CS-like cells. Flubendazole inhibited breast cancer cells proliferation in dose- and time-dependent manner and delayed tumor growth in xenograft models by intraperitoneal injection. Importantly, flubendazole reduced CD44high/CD24low subpopulation and suppressed the formation of mammosphere and the expression of self-renewal related genes including c-myc, oct4, sox2, nanog and cyclinD1. Moreover, we found that flubendazole induced cell differentiation and inhibited cell migration. Consistently, flubendazole reduced mesenchymal markers (β-catenin, N-cadherin and Vimentin) expression and induced epithelial and differentiation marker (Keratin 18) expression in breast cancer cells. Mechanism study revealed that flubendazole arrested cell cycle at G2/M phase and induced monopolar spindle formation through inhibiting tubulin polymerization. Furthermore, flubendazole enhanced cytotoxic activity of conventional therapeutic drugs fluorouracil and doxorubicin against breast cancer cells. In conclusion, our findings uncovered a remarkable effect of flubendazole on suppressing breast CS-like cells, indicating a novel utilization of flubendazole in breast cancer therapy.

EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling

“…For example, the E3 ligase Skp2, a critical factor in cell-cycle progression, restricted cancer progression and metastasis [63]. Flubendazole treatment arrests cells in the G2/M phase, suppresses CS-like cell migration, and induces breast cancer differentiation [65]. Here, we identified a novel function of EZH2 based on the finding that silencing EZH2 arrested CCS-like cells in the G1/S phase (Figure 7A-7B).…”

“…This finding suggested that cycling CS-like cells are a target for eradicating cancer [62]. Indeed, accumulating studies have highlighted that arresting the cell cycle in CS-like cells decreases tumorigenesis [63–65]. For example, the E3 ligase Skp2, a critical factor in cell-cycle progression, restricted cancer progression and metastasis [63].…”

High expression of Collagen Triple Helix Repeat Containing 1 (CTHRC1) facilitates progression of oesophageal squamous cell carcinoma through MAPK/MEK/ERK/FRA-1 activation

“…Through transcriptome sequencing and extensive step-by-step in vitro analyses, we identified Cyclin D1 and snail1 as major downstream effectors of FRA-1, accounting for the CTHRC1-mediated regulation of proliferation and motility in ESCC cells. The most prominent function of snail1 in cancer cells is to induce the epithelial-mesenchymal transition (EMT) [46, 47], and it was recently reported that CTHRC1 upregulated snail1 to induce EMT by activating the Wnt/β-catenin signalling pathway in epithelial ovarian cancer [48]. Interestingly, we did not observe any meaningful alteration in β-catenin expression or in hallmarks of EMT [49], namely, E-Cadherin and vimentin, after CTHRC1 knockdown in ESCC cell lines (Additional file 5: Figure S3), suggesting that an alternative hypothesis is needed to explain findings for ESCC.…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Similar antitumor activity of mebendazole was found in gastric cancer, medulloblastoma, glioblastoma, leukemia and myeloma as well as in breast cancer stem cell-like cells [22][23][24][25][26]. Mebendazole potently inhibited hedgehog (Hh) signaling and slowed the growth of Hh-driven human medulloblastoma cells at clinically attainable concentrations [27].…”

“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”