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

• Published in: Oncogene 2024-11, Vol.43 (46), p.3378-3387
• Main Authors: Duysak, Taner, Kim, Kwangsoo, Yun, Misun, Jeong, Jae-Ho, Choy, Hyon E.
• Format: Article
• Language: English
• Subjects: 13/2; 42/109; 42/44; 45/44; 45/77; 631/326; 631/337; 631/67/1059/2325; 64/60; 82/1; 82/16; 82/80; 82/83; Amino acids; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; Arginine; Arginine - metabolism; Argininosuccinate lyase; Argininosuccinate Synthase - genetics; Argininosuccinate Synthase - metabolism; Autophagy; Auxotrophy; Cancer; Cancer therapies; Cell Biology; Cell death; Cell Line, Tumor; Chloroquine; Chloroquine - pharmacology; Chloroquine - therapeutic use; Citrulline; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - microbiology; Colorectal Neoplasms - pathology; Enzymes; Female; Human Genetics; Humans; Hydrolases - genetics; Hydrolases - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Oncology; Salmonella; Salmonella - genetics; Salmonella Gallinarum; Tumors
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03176-0

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.