Targeted bacteria-mediated therapy of mouse colorectal cancer using baicalin, a natural glucuronide compound, and E. coli overexpressing β–glucuronidase

Abstract

The side effects of common chemotherapeutic drugs that damage healthy tissues account for one of the most important problems in cancer research that needs careful addressing. Bacterial-Directed Enzyme Prodrug Therapy (BDEPT) is a promising strategy that uses bacteria to direct a converting enzyme to the tumor site and activate a systemically injected prodrug selectively within the tumor; so that the side effects of the therapy would significantly decrease. In this study, we evaluated the efficacy of baicalin, a natural compound, as a glucuronide prodrug in association with an engineered strain of Escherichia coli DH5α harboring the pRSETB-lux/βG plasmid in a mouse model of colorectal cancer. E. coli DH5α-lux/βG was designed to emit luminescence, and overexpress the β-glucuronidase. Unlike the non-engineered bacteria, E. coli DH5α-lux/βG showed the ability to activate baicalin, and the cytotoxic effects of baicalin on the C26 cell line were increased in the presence of E. coli DH5α-lux/βG. Analyzing the tissue homogenates of mice bearing C26 tumors inoculated with E. coli DH5α-lux/βG indicated the specific accumulation and multiplication of bacteria in the tumor tissues. While both baicalin and E. coli DH5α-lux/βG could inhibit tumor growth as monotherapy, an enhanced inhibition was observed when animals were subjected to combination therapy. Moreover, no significant side effects were observed after histological investigation. The results of this study indicate that baicalin has the capability of being used as a suitable prodrug in the BDEPT, however further research is required before it can be applied in the clinic.