مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Salmonella-mediated cancer therapy: a therapeutic candidate for glioma
Salmonella-mediated cancer therapy: a therapeutic candidate for glioma
Zahra Naziri,1Zahra Gholizadeh Farshi,2,*Zahra Rezaei,3
1. Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran 2. Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran 3. Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
Introduction: One of the most dangerous diseases in the world is cancer, and it is predicted that by 2030, more than 26 million people will be severely at risk of contracting it. The most common malignant tumor of the central nervous system is glioma, and 50% of patients suffer from its most aggressive type, glioblastoma. Despite recent advances in chemotherapy and surgical techniques, median survival rates are still consistently low.
At the end of the 19th century, Wilhelm Bosch and William Coley discovered that live bacteria might cause tumor regression and increase patient survival, which led to the introduction of bacteria-mediated cancer therapy.
Methods: Today, it is known that the gram-negative bacterium Salmonella can be qualified as a candidate for cancer therapy. However, this bacterium can have severe side effects, which are chiefly related to its lipid A endotoxin, which is the product of the msbB gene. By deleting virulence genes of Salmonella, its complications can be reduced, but this should be done in such a way that it maintains a high affinity for solid tumors. In the new strain of this bacterium, two targeted deletions have been made in the region of msbB and purM genes, which have led to a decrease in lipid A toxicity and dependence on purine supplementation, respectively. Moreover, this new strain contains a non-synonymous single nucleotide polymorphism in the cheY gene, which reduces its capacity for chemotaxis. This gene present in the CheA/CheY two-component system, which is crucial for the motility and spread of bacteria in the tumor, as well as the chemotaxis response. However, studies showed that tumor colonization was not affected by the absence of CheY protein.VNP20009, which is a modified and new strain of SalmonellaTyphimurium, is significantly more capable of multiplying in tumors than in healthy tissues. Also, mutated Salmonella has the ability to enter the deep areas of tumors where common drugs cannot reach.
In Salmonella infection, toll-like receptors (TLRs) that can recognize the molecular patterns of Gram-negative bacteria are first activated, then the host's immune system is stimulated and antitumor activities are developed. After infection, a cascade of cellular signals is activated that triggers a storm of cytokines and chemokines, followed by an influx of immune cells into tumor tissues. Tumor cells that were damaged by Salmonella infection release ATP, which causes the activation of NLRP3 inflammasome and increases IL-1β, IL-18, and TNF-α, which are inflammatory cytokines and lead to tumor regression. Inflammasome activation can occur directly by Salmonella LPS or by ATP signals and phagocytosis of damaged tumor cells.
Results: Salmonella was first used in preclinical studies in 2000 for the treatment of advanced tumors but was discontinued in the first phase of clinical trials due to low tumor regression and the occurrence of side effects at high doses. However, intravenous infusion of VNP20009 increased circulating pro-inflammatory cytokines and caused significant colonization in tumor biopsies of 12% of patients. Therefore, with more research on the weaknesses of previous trials, the results of future clinical trials will be different and better. One of the obstacles that effect on the ability of VNP20009 in tumor targeting is a point mutation in the cheY gene. By replacing the mutant cheY with its wild-type sequence, the chemotactic ability of this strain was increased with an efficiency of 69%.In addition, by restoring the msbB gene in VNP20009 CheY+, optimization has been done, which has increased the chemotactic mobility. Another method that helps Salmonella to target tumors is to induce surface modifications in this bacterium, such as the display of arginine-glycine-aspartate (RGD) peptide sequences in the outer membrane protein A of Salmonella Typhimurium. Through this peptide, Salmonella can effectively bind to αvβ3, which is present in most tumor cells.
Conclusion: In conclusion, modified Salmonella has significant potential for bacteria-mediated cancer therapy. Many strains of Salmonella have so far been demonstrated to successfully reduce the growth of tumors when used in conjunction with other treatments.