Year-end Sale % OFF 
Abstract
BackgroundSignal 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.MethodsIn 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.ResultsFlubendazole 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.ConclusionsTaken 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.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is an oncogene, which upregulates in approximately 70% of human cancers
Flubendazole inhibits Colorectal cancer (CRC) cells proliferation The antitumor activity of flubendazole was evaluated by analyzing its inhibitory effects on cell proliferation (Fig. 1a)
Our findings revealed that flubendazole effectively reduces the viability of CRC cells (HCT116, RKO and SW480) in a concentration-dependent manner, with an The half maximal inhibitory concentrations (IC50) of 2–5 μM (Fig. 1b)
Summary
Signal transducer and activator of transcription 3 (STAT3) is an oncogene, which upregulates in approximately 70% of human cancers. The STAT3 signaling pathway, which may be triggered by cancer cells, has been implicated in the autophagic process. The high incidence rate of CRC maintains a significant increase [1, 2]. 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 [3]. The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactive in most of human cancers including CRC [5]. Compelling evidence has demonstrated the crucial role of STAT3 in promoting tumor cell proliferation, angiogenesis, metastasis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
