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Antitumor therapeutic effects of a genetically engineered Salmonella typhimurium harboring TNF-α in mice

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Abstract

Although the use of TNF-α in the treatment of cancer is restricted due to its non-specific cytotoxicity and narrow range of applications to different cancers in clinical trials, we investigated a safe anti-cancer drug by the use of engineered bacterial capsule harboring TNF-α. The engineered bacterial capsule was designed to target cancer cells, promote a tumor-suppressive environment, and increase the efficacy of existing cancer treatments, including chemotherapy, radiotherapy, and cell therapy. The engineered bacterial capsule was constructed with Salmonella capsulizing TNF-α protein, which was produced and capsulized by Salmonella to reduce side effects of the protein. This bacterial capsule induced a tumor-suppressive environment through the activation of natural killer cells. Engineered bacterial capsule invaded tumor cells, released TNF-α, and induced apoptosis of tumor cells without apparent side effects. In a murine melanoma model, the bacterial capsule of TNF-α significantly inhibited tumor growth by 80–100% and prolonged the survival of the mice. When tested in combination with chemotherapy (cisplatin), antibiotics, and vaccine, recombinant microbial treatment increased the anti-tumor effects of existing therapies. The anti-tumor effects of the bacterial capsule of TNF-α were also observed in cervical cancer, melanoma, breast cancer, colon cancer, and renal carcinoma. These results suggest that the bacterial capsule of TNF-α is a promising strategy for TNF-α treatment.

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Acknowledgments

This work was supported by KFDA and Korea Science & Engineering Foundation (Grant No. E00156).

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea. (A090228)

We are grateful to YuChang Park, YeSu Ju, and HaNa Nim for their expert, technical assistance.

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, 5-ga Anam-dong, SeoungBuk-gu, Seoul, 136-701, Republic of Korea

    Won Suck Yoon & Yong Keun Park

  2. Office of Research, Korea University, Seoul, Republic of Korea

    Won Suck Yoon

  3. Department of Pathology, Korea University College of Medicine, Korea University, Seoul, Republic of Korea

    Yang Seok Chae

  4. Rice University, Houston, TX, USA

    Juyeon Hong

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  1. Won Suck Yoon
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Correspondence to Yong Keun Park.

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Fig. S1

Survival of recombinant bacteria in tumor-bearing mice. B16F10 tumor-bearing C57BL6 mice were subcutaneously inoculated with 1 × 108 S. typhimurium harboring TNF-α next to tumor. At 1, 12, and 24 h after treatment, the tumor region was homogenized. Tumor cell lysates were cultivated and the percent survival of recombinant bacteria was calculated. (DOC 71 kb)

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Yoon, W.S., Chae, Y.S., Hong, J. et al. Antitumor therapeutic effects of a genetically engineered Salmonella typhimurium harboring TNF-α in mice. Appl Microbiol Biotechnol 89, 1807–1819 (2011). https://doi.org/10.1007/s00253-010-3006-4

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