In addition, STAT3 is associated with tumor cell apoptosis through the regulation of BCL2, BAX, MCL1 and survivin ( BIRC5). Compelling evidence has demonstrated the crucial role of STAT3 in promoting tumor cell proliferation, angiogenesis, metastasis and resistance to therapies by regulating the expression of correlative genes such as vascular endothelial growth factor (VEGF).
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The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactive in most of human cancers including CRC.
Therefore, researchers have intense interest in finding new strategies aimed at improving treatment effectiveness and prognosis. Despite the many advances in CRC research, including screening and treatment, the overall survival rate of patients with CRC is still low and the rate of tumor recurrence remains currently invariable. Meanwhile, the high incidence rate of CRC maintains a significant increase. Flubendazole maybe a novel anticancer drug and offers a distinctive therapeutic strategy in neoadjuvant chemotherapy of CRC.Ĭolorectal cancer (CRC) is one of the most common digestive tract malignancies worldwide, which is among the leading causes of cancer death. Taken together, these results indicate that flubendazole exerts antitumor activities by blocking STAT3 signaling and inevitably affects the autophagy pathway. In addition, flubendazole displayed a synergistic effect with the chemotherapeutic agent 5-fluorouracil in the treatment of CRC. These processes induced potent cell apoptosis in CRC cells. 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. Resultsįlubendazole 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. Additionally, the expression of STAT3 and mTOR was analyzed in paired colorectal cancer and normal tissues collected from clinical patients. 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.
The inhibition of cell proliferation in vitro by flubendazole was evaluated using a clonogenic assay and the MTT assay. 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. Moreover, the STAT3 signaling pathway, which may be triggered by cancer cells, has been implicated in the autophagic process. Autophagy is an evolutionarily conserved process which maintains cellular homeostasis and eliminates damaged cellular components. Signal transducer and activator of transcription 3 (STAT3) is an oncogene, which upregulates in approximately 70% of human cancers.