Abstract
Anticancer treatment strategies using bacteria as a vector are currently expanding with the development of anticancer drugs. Here, we present a research strategy to develop anticancer drugs using bacteria that contain miRNAs. We also present a strategy for the development of novel bacterial anticancer drugs in combination with radiation. Salmonella strains expressing miRNA were produced by modifying the miRNA expression vector encoding INHA, a radiation-resistant gene developed previously. The anticancer effect of INHA was confirmed using skin cancer cell lines. We also tested a combination strategy comprising bacteria and radiation for its anticancer efficacy against radiation-resistant mouse melanoma to increase the efficacy of radiation therapy as a novel strategy. The recombinant strain was confirmed to promote effective cell death even when combined with radiation therapy, which exerts its cytotoxicity by enhancing reactive oxygen species production. Moreover, a combination of bacterial and radiation therapy enhanced radiotherapy efficacy. When combined with radiation therapy, bacterial therapy exhibited effective anti-cancer properties even when administered to animals harboring radiation-resistant tumors. This strategy may promote the secretion of cytokines in cells and more effectively reduce the number of bacteria remaining in the animal. Thus, this study may lead to the development of a strategy to improve the effectiveness of radiation therapy using Salmonella expressing cancer-specific miRNA for intractable cancers such as those resistant to radiation.
Highlights
Over the past two decades, many studies have shown that Salmonella and tumor microenvironments are closely connected with respect to hypoxia [1]
To suppress the INHA gene that is overexpressed in radiation-resistant cancers, we constructed the Salmonella strains expressing the INHA miRNA operated by the Salmonella promoter
A system was designed for delivering miRNA using the strain to target cancer cells through a prokaryotic expression system
Summary
Over the past two decades, many studies have shown that Salmonella and tumor microenvironments are closely connected with respect to hypoxia [1]. Salmonella preferentially accumulates in tumors of the liver at a ratio of 1000:1, and the rapid growth of tumors results in low oxygen, low pH, and necrosis [2,3,4]. Using these characteristics of Salmonella and tumor microenvironments, various Salmonella strains or those carrying a variety of effector genes have been developed and examined [5,6]. It was confirmed that colon cancer and skin cancer were suppressed by miRNAs facilitating the expression of inhibin alpha [12,13]. The inhibin gene is overexpressed in radiation-resistant skin cancer [14,15]; it is necessary to analyze the correlation between radiation therapy and these genes
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