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The exosome secretion inhibitor neticonazole suppresses intestinal dysbacteriosis-induced tumorigenesis of colorectal cancer

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Summary

Colorectal cancer (CRC) is the most frequently encountered malignancy associated with the rectum or colon, and accumulating evidences have implicated intestinal dysbacteriosis (IDB, disruption of gut microbiome) and exosomes in the pathology of CRC. We aimed to investigate the effect of IDB on exosome secretion in a CRC xenograft mouse model. An IDB mouse model was established and was inoculated with the CRC cell line SW480 as a xenograft tumor. Tumor growth was monitored for 15 days in sham and IDB mice, after which blood was collected to assess serum exosome secretion. A novel exosome secretion inhibitor, neticonazole, was administered to IDB mice bearing CRC xenograft tumors, followed by monitoring of tumor growth and mouse survival. Western blot analysis was performed in xenograft tumors to investigate the underlying molecular mechanism. IDB promoted CRC xenograft tumor growth and exosome secretion, which could be inhibited by the exosome secretion inhibitor neticonazole. Moreover, neticonazole treatment significantly improved the survival of IDB mice with CRC xenograft tumors, likely through increasing apoptosis of CRC xenograft tumor cells. The exosome secretion inhibitor neticonazole may serve as a promising therapeutic candidate against CRC by suppressing IDB-induced CRC tumorigenesis.

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Abbreviations

CRC:

Colorectal cancer

IDB:

Intestinal dysbacteriosis

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Funding

This study was supported by the National Natural Science Foundation of China (81272720).

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Author notes

  1. Lei Gu, Yidong Xu and Wangyan Xu contributed equally to this work

Authors and Affiliations

  1. Department of General Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, China

    Lei Gu, Yidong Xu, Cong Li & Zhongchen Liu

  2. Anhui University of Science and Technology, Huainan, 232001, Anhui, China

    Wangyan Xu & Hui Su

  3. School of Medicine Tongji University, Shanghai, 200092, China

    Meng Li

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  1. Lei Gu
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  2. Yidong Xu
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  6. Cong Li
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Correspondence to Zhongchen Liu.

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Gu, L., Xu, Y., Xu, W. et al. The exosome secretion inhibitor neticonazole suppresses intestinal dysbacteriosis-induced tumorigenesis of colorectal cancer. Invest New Drugs 38, 221–228 (2020). https://doi.org/10.1007/s10637-019-00759-7

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  • DOI: https://doi.org/10.1007/s10637-019-00759-7

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