Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy

Abstract

Background Signal transducer and activator of transcription 3 (STAT3) is an oncogene, which upregulates in approximately 70% of human cancers. Autophagy is an evolutionarily conserved process which maintains cellular homeostasis and eliminates damaged cellular components. Moreover, the STAT3 signaling pathway, which may be triggered by cancer cells, has been implicated in the autophagic process. Methods In this study, we found that the anthelmintic flubendazole exerts potent antitumor activity in three human colorectal cancer (CRC) cell lines and in the nude mouse model. The inhibition of cell proliferation in vitro by flubendazole was evaluated using a clonogenic assay and the MTT assay . Western blot analysis, flow cytometry analysis, siRNA growth experiment and cytoplasmic and nuclear protein extraction were used to investigate the mechanisms of inhibiting STAT3 signaling and activation of autophagy induced by flubendazole. Additionally, the expression of STAT3 and mTOR was analyzed in paired colorectal cancer and normal tissues collected from clinical patients. Results Flubendazole blocked the IL6-induced nuclear translocation of STAT3, which led to inhibition of the transcription of STAT3 target genes, such as MCL1 , VEGF and BIRC5 . In addition, flubendazole also reduced the expression of P-mTOR, P62, BCL2, and upregulated Beclin1 and LC3-I/II, which are major autophagy-related genes. These processes induced potent cell apoptosis in CRC cells. In addition, flubendazole displayed a synergistic effect with the chemotherapeutic agent 5-fluorouracil in the treatment of CRC. Conclusions Taken together, these results indicate that flubendazole exerts antitumor activities by blocking STAT3 signaling and inevitably affects the autophagy pathway. Flubendazole maybe a novel anticancer drug and offers a distinctive therapeutic strategy in neoadjuvant chemotherapy of CRC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1303-z) contains supplementary material, which is available to authorized users.

Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer

“…Mechanistically, flubendazole may also target NF-κB signaling, which is required for esophageal squamous carcinoma cell survival 17 . In colorectal and breast cancer cells, flubendazole exerts anti-tumor and anti-metastatic activities by inhibiting STAT3 22 , 26 .…”

“…Depending on the context, it may positively or negatively influence cancer metastasis 48 , which is ultimately the primary cause of cancer-associated mortality. A number of studies have indicated a close relationship between flubendazole and autophagy, though the exact mechanism has been not characterized, especially in the context of TNBC 22 , 28 .…”

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

“…Supplementary Table 1 ( 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 ) summarizes the antitumorigenicity of benzimidazole anthelmintics on cancer cell lines. Benzimidazole anthelmintics inhibit the progression of cancer through a variety of mechanisms.…”

“…Mebendazole had no effects on normal fibroblasts compared with adrenocortical carcinoma cells ( 79 ). The inhibitory effect of flubendazole was limited in normal human liver cells and cardiomyocytes compared with colorectal cancer cells ( 34 ). Fenbendazole showed little effect on normal human bronchial epithelial cells, normal immortalized human prostate cells, and primary mouse fibroblasts compared with lung cancer cells, as the IC50 values for fenbendazole were several fold higher in these normal cells compared with cancer cell lines ( 38 ).…”

Biology of Glioblastoma Multiforme—Exploration of Mitotic Catastrophe as a Potential Treatment Modality

“…Accordingly, tumor cell populations exposed to MC-inducing agents are likely to respond with a significant degree of heterogeneity including the appearance of several cell phenotypes whose relative proportions and fates may ultimately reflect the evolutionary status and the nature of the particular tumor [ 77 , 78 , 79 ]. Thus several research groups have reported that tumor cells exposed to benzimidazoles in vitro become polyploid, aneuploid or senescent, upregulate autophagy and die via apoptosis or necrosis [ 80 , 81 , 82 ]. In Figure 1 , two possible scenarios of benzimidazole-exposed GBM cells responses are shown including cell morphologies as well as select molecular players.…”