Development of Oxytolerant Salmonella typhimurium Using Radiation Mutation Technology (RMT) for Cancer Therapy

Area of Science:

• Oncolytic Virotherapy
• Bacterial Cancer Therapy
• Radiation Biology

Background:

• Salmonella typhimurium (S. typhimurium) has potential as an anti-cancer agent, but its efficacy is limited by reduced invasive and replicative activities within cancer cells.
• Developing attenuated Salmonella strains with enhanced tumor-targeting capabilities is crucial for effective cancer therapy.

Purpose of the Study:

• To engineer an oxytolerant, attenuated Salmonella strain capable of delivering anti-cancer agents and enhancing radiation therapy.
• To evaluate the anti-tumor efficacy of the engineered strain in combination with radiation in a murine tumor model.

Main Methods:

• Radiation mutation technology (RMT) was used to develop an oxytolerant attenuated Salmonella strain (KST0650) from a parental strain (KST0649).
• KST0650 was engineered to express a radiation-inducible pro-apoptotic protein (sATF6) via a plasmid, creating strain KST0652.
• The Salmonella type III secretion system (T3SS) was utilized for intracellular delivery of sATF6 into cancer cells and tumor tissues.

Main Results:

• The KST0650 strain exhibited 20-times higher replication activity in CT26 cancer cells and reduced virulence compared to the parental strain.
• KST0652 demonstrated effective migration into tumor tissues in mice and dose-dependent sATF6 expression in response to radiation.
• Combination treatment with KST0652 and radiation resulted in a synergistic anti-tumor effect, achieving complete tumor growth inhibition and protection from death in a murine model.

Conclusions:

• RMT is an effective method for developing advanced anti-tumor Salmonella strains for targeted delivery of anti-cancer agents.
• The engineered Salmonella strain KST0652, combined with radiation, shows significant promise as a synergistic anti-cancer therapeutic strategy.