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Enhanced anti-cancer efficacy of arginine deaminase expressed by tumor-seeking Salmonella Gallinarum

Oncogene volume 43, pages 3378–3387 (2024)Cite this article

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Abstract

Amino acid deprivation, particularly of nonessential amino acids that can be synthesized by normal cells but not by cancer cells with specific defects in the biosynthesis pathway, has emerged as a potential strategy in cancer therapeutics. In normal cells, arginine is synthesized from citrulline in two steps via two enzymes: argininosuccinate synthetase (ASS1) and argininosuccinate lyase. Several cancer cells exhibit arginine auxotrophy due to the loss or down-regulation of ASS1. These cells undergo starvation-induced cell death in the presence of arginine-degrading enzymes such as arginine deaminase (ADI). Thus, ADI has emerged as a potential therapeutic in cancer therapy. However, the use of ADI has two major disadvantages: ADI of bacterial origin is strongly antigenic in mammals, and ADI has a short circulation half-life (∼5 h). In this study, we engineered tumor-targeting Salmonella Gallinarum to express and secrete ADI and deployed this strain into mice implanted with ASS1-defective mouse colorectal cancer (CT26) through an intravenous route. A notable antitumor effect was observed, suggesting that the disadvantages were overcome as ADI was expressed constitutively by tumor-targeting bacteria. A combination with chloroquine, which inhibits the induction of autophagy, further enhanced the effect.

Anti-cancer effect of Salmonella Gallinarum expressing an arginine deiminase (ADI) on arginine-dependent tumors in situ.

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Fig. 1: Engineering ADI-expressing S. Gallinarum and evaluation of its anticancer activity against different cancer cell lines in vitro.
Fig. 2: Expression and secretion of PelB-ADI by intratumoral S. Gallinarum harboring pTAC_PelB::ADI, and its antitumor efficacy in BALB/c mice bearing CT26 colon carcinoma xenografts.
Fig. 3: Effect of combination treatment of S. Gallinarum carrying different plasmids with purified ADI.
Fig. 4: Therapeutic efficacy of combination treatment with S. Gallinarum expressing PelB-ADI and CQ.

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Data availability

The data and code underlying the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation(NRF) funded by the Korean government (MSIT) (No. NRF-2020M3A9G3080282). MY was supported by the World Institute of Kimchi (grant numbers: KE2403-1), funded by the Ministry of Science and ICT, Republic of Korea.

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Authors and Affiliations

  1. Department of Microbiology, Chonnam National University Medical School, Gwangju, 61468, Korea

    Taner Duysak, Jae-Ho Jeong & Hyon E. Choy

  2. Odysseus Bio, Basic Medical Research Building, Chonnam National University Medical College, 322 Seoyang-ro, Hwasun, Jeonnam, 58128, Korea

    Taner Duysak, Kwangsoo Kim & Hyon E. Choy

  3. Technology Innovation Research Division, World Institute of Kimchi, Gwangju, 61755, Republic of Korea

    Misun Yun

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Conceptualization, HEC and H-HJ; methodology, KK; data curation, TD; writing—original draft preparation, TD; writing—review and editing, HEC and MY; funding acquisition, J-HJ. All authors have read and agreed to the published version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jae-Ho Jeong or Hyon E. Choy.

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The animal study protocol was approved by the Ethics Committee of Chonnam National University–Institutional Animal Use and Care Committee (CNU IACUC-H-2020-7).

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Duysak, T., Kim, K., Yun, M. et al. Enhanced anti-cancer efficacy of arginine deaminase expressed by tumor-seeking Salmonella Gallinarum. Oncogene 43, 3378–3387 (2024). https://doi.org/10.1038/s41388-024-03176-0

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