Abstract
The gram-negative facultative anaerobic bacteria Salmonella enterica serovar Typhimurium (hereafter S. Typhimurium) has always been considered as one candidate of anti-tumor agents or vectors for delivering drug molecules. In this study, we compared several widely studied S. Typhimurium strains in their anti-tumor properties aiming to screen out the best one for further optimization and use in cancer therapy. In terms of the motility, virulence and anti-tumor efficacy, the three strains 14028, SL1344, and UK-1 were similar and obviously better than LT-2, and UK-1 showed the best phenotypes among them. Therefore, the strain UK-1 (D) was selected for the following studies. Its auxotrophic mutant strain (D1) harboring ∆aroA and ∆purM mutations was further optimized through the modification of lipid A structure, generating a new strain named D2 with stronger immunostimulatory activity. Finally, the ∆asd derivative of D2 was utilized as one live vector to deliver anti-tumor molecules including the angiogenesis inhibitor endostatin and apoptosis inducer TRAIL and the therapeutic and toxic-side effects were evaluated in mouse models of colon carcinoma and melanoma. After intraperitoneal infection, engineered Salmonella bacteria equipped with endostatin and/or TRAIL significantly suppressed the tumor growth and prolonged survival of tumor-bearing mice compared to PBS or bacteria carrying the empty plasmid. Consistently, immunohistochemical studies confirmed the colonization of Salmonella bacteria and the expression of anti-tumor molecules inside tumor tissue, which were accompanied by the increase of cell apoptosis and suppression of tumor angiogenesis. These results demonstrated that the beneficial anti-tumor efficacy of attenuated S. Typhimurium bacteria could be improved through delivery of drug molecules with powerful anti-tumor activities.
Highlights
Great advances have been made in cancer treatment and detection, cancer is still one of the leading causes of death worldwide
Typhimurium strains 14028, SL1344, LT-2, UK-1, and SL7207 were indicated by A, B, C, D and E for short, respectively
Outer membrane proteins (OMPs) purified from these strains were stained on SDS-PAGE gel using coomassie brilliant blue and similar bands were shown except that one more protein of about 60 kDa was present in LT-2
Summary
Great advances have been made in cancer treatment and detection, cancer is still one of the leading causes of death worldwide. Targeted cancer therapy is urgently needed now. Optimized Salmonella for Cancer Therapy cancer has been documented for over 100 years (Forbes et al, 2018). Many facultative or obligate anaerobic bacteria, such as Clostridium (Malmgren and Flanigan, 1955), Bifidobacterium (Kohwi et al, 1978), Escherichia coli (Stritzker et al, 2007), and Salmonella (Low et al, 1999), have been shown to possess intrinsic tumor-targeting and tumor-killing activities. The anti-tumor potential of facultative anaerobic Salmonella Typhimurium has been extensively studied in the past three decades. Typhimurium can directly exert tumorkilling activities or act as a live delivery vector for a wide variety of anti-tumor molecules (Liang et al, 2021)
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