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Flubendazole demonstrates valid antitumor effects by inhibiting STAT3 and activating autophagy

Shichong Lin^1,2, Lehe Yang^1,2, Yulei Yao^1,2

¹School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People's Republic of China.

Journal of Experimental & Clinical Cancer Research : CR

|July 10, 2019

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.

Insights

Flubendazole, an anthelmintic, shows potent antitumor effects against colorectal cancer by inhibiting STAT3 signaling and activating autophagy. This drug may offer a new therapeutic strategy for colorectal cancer treatment.

Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

Signal transducer and activator of transcription 3 (STAT3) is an oncogene implicated in ~70% of human cancers.
Autophagy is a cellular homeostasis process that can be influenced by STAT3 signaling in cancer.
STAT3 pathway activation is observed in cancer cells, highlighting its role in tumorigenesis.

Purpose of the Study:

To investigate the antitumor activity of flubendazole in colorectal cancer (CRC).
To elucidate the mechanisms underlying flubendazole's effects on STAT3 signaling and autophagy.
To evaluate flubendazole's potential as a novel therapeutic agent for CRC.

Main Methods:

In vitro and in vivo models of colorectal cancer (CRC) were used.
Flubendazole's effects on cell proliferation were assessed using clonogenic and MTT assays.
Western blot, flow cytometry, and siRNA were employed to analyze STAT3 signaling, autophagy markers, and protein expression.

Main Results:

Flubendazole inhibited IL6-induced STAT3 nuclear translocation and suppressed STAT3 target genes (MCL1, VEGF, BIRC5).
Flubendazole modulated autophagy markers (reduced P-mTOR, P62, BCL2; upregulated Beclin1, LC3-I/II) and induced apoptosis in CRC cells.
Flubendazole demonstrated synergistic effects with 5-fluorouracil in CRC treatment.

Conclusions:

Flubendazole exhibits antitumor activity by concurrently inhibiting STAT3 signaling and modulating the autophagy pathway.
Flubendazole represents a potential novel anticancer drug for colorectal cancer.
This study suggests flubendazole as a distinctive therapeutic strategy, particularly in neoadjuvant chemotherapy for CRC.

Read full analysis

Keywords:

Apoptosis Autophagy Colorectal cancer Flubendazole STAT3

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