Microbial-based therapy of cancer: current progress and future prospects

Abstract

The use of bacteria in the regression of certain forms of cancer has been recognized for more than a century. Much effort, therefore, has been spent over the years in developing wild-type or modified bacterial strains to treat cancer. However, their use at the dose required for therapeutic efficacy has always been associated with toxicity problems and other deleterious effects. Recently, the old idea of using bacteria in the treatment of cancer has attracted considerable interest and new genetically engineered attenuated strains as well as microbial compounds that might have specific anticancer activity without side effects are being evaluated for their ability to act as new anticancer agents. This involves the use of attenuated bacterial strains and expressing foreign genes that encode the ability to convert non-toxic prodrugs to cytotoxic drugs. Novel strategies also include the use of bacterial products such as proteins, enzymes, immunotoxins and secondary metabolites, which specifically target cancer cells and cause tumor regression through growth inhibition, cell cycle arrest or apoptosis induction. In this review we describe the current knowledge and discuss the future directions regarding the use of bacteria or their products, in cancer therapy.

Keywords: Pseudomonas aeruginosa; anticancer agents from microbial sources; azurin; cancer therapy; drug development; multi-targeting drugs in cancer therapy.

Figure 1

The mode of action of azurin in the induction of apoptosis and growth inhibition of a MCF-7 breast cancer cell is shown schematically. Azurin can enter the cancer cell to form a complex with tumor suppressor protein p53 (4 azurin molecules per 1 p53 molecule), stabilizing it and enhancing its intracellular level, which leads to apoptosis via caspase-mediated mitochondrial cytochrome c release pathways (A). Azurin can also bind avidly to the surface—exposed receptor tyrosine kinase EphB2, interfering in its binding with the ligand ephrinB2, and thereby preventing cell signaling that promotes cancer cell growth (B).

Figure 2

Studies of complex formation between the bacterial protein azurin and the transcription factor p53. (A) Binding studies using Isothermal Titration Calorimetry and Atomic Force Microscopy. (B and C) Docking studies and free energy simulation for the interaction between azurin and p53 N-terminal (p53-NT) and azurin and p53 DNA binding domain (p53-DBD).