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.
Aim and Objective :
Lung cancer is the most common cancer which contributes to the majority of death caused by
cancer where non-small-cell lung cancer (NSCLC) accounts for approximately 85%. To treat NSCLC, STAT3 has been
identified as a target with therapeutic potential. The neobavaisoflavone (NBIF) is one of the flavonoids of traditional
Chinese medicine Psoralea corylifolial.
Materials and Methods:
Human NSCLC cell lines, PC-9, H460 and A549, were applied to determine NBIF’s antiproliferative effects through cell viability and colony formation detection. The effect of NBIF on cell apoptosis was
determined through Flow cytometry-based assay. Western blotting was used in this study to confirm the levels of P-STAT3
and Bcl-2 and Bax which are apoptotic proteins.
Results:
It was observed that NBIF could decrease the cell viability and migration and induce apoptosis in human NSCLC
cell lines dose-dependently. Levels of P-STAT3, as well as the downstream signals of STAT3 pathway, were
downregulated, suggesting that the tumor-suppression effects of NBIF might be related to the inhibition of STAT3
signaling. Furthermore, NBIF could contribute to the upregulation of BAX and downregulation of BCL2.
Conclusion:
NBIF might perform the anti-NSCLC efficacy as a result of the inhibition on STAT3 pathway. Besides, our
work suggests that NBIF could provide therapeutic alternatives for NSCLC.
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