Bacteria-derived chimeric toxins as potential anticancer agents

Abstract

Cancer is one of the major causes of death globally, requiring everlasting efforts to develop novel, specific, effective, and safe treatment strategies. Despite advances in recent years, chemotherapy, as the primary treatment for cancer, still faces limitations such as the lack of specificity, drug resistance, and treatment failure. Bacterial toxins have great potential to be used as anticancer agents and can boost the effectiveness of cancer chemotherapeutics. Bacterial toxins exert anticancer effects by affecting the cell cycle and apoptotic pathways and regulating tumorigenesis. Chimeric toxins, which are recombinant derivatives of bacterial toxins, have been developed to address the low specificity of their conventional peers. Through their targeting moieties, chimeric toxins can specifically and effectively detect and kill cancer cells. This review takes a comprehensive look at the anticancer properties of bacteria-derived toxins and discusses their potential applications as therapeutic options for integrative cancer treatment.

Keywords: affibody; anticancer; bacteria-derived chimeric toxin; bacterial toxins; chimeric toxin; exotoxin A; immunotoxin; ligand-based immunotoxins.

Figure 1

The structure of chimeric anticancer toxins (CATs). These chimeric toxins contain two distinct components. (A) A target moiety that is responsible for recognizing cancer-specific receptors on tumor cells. This part can be derived from different types of biomolecules, including antibodies and their derivatives, microbial toxins, antimicrobial peptides, and immunoligands. (B) A cytolethal moiety that is responsible for killing the host cell. Chimeric toxins can be developed from the primary toxins that may be synthetic or obtained from different sources, including microbes, plants, and animals.

Figure 2

The effects of bacteria-derived toxins on cancerous cells. (A) Ras/Rap1-specific endopeptidase (RRSP) toxin secreted by Vibrio vulnificus blocks the RAS signal transduction pathway, leading to the abrogation of key signaling modulators (especially Raf) and a reduction in cell proliferation, differentiation, and, ultimately, survival. (B) Apoptosis induced by excessive osmotic pressure caused by the action of pore-forming toxins such as Clostridium perfringens enterotoxin (CPE) and Aeromonas hydrophila aerolysin. (C) The receptor-mediated internalization of diphtheria toxin (DT)-based immunotoxin blocks protein synthesis via inducing the ADP-ribosylation of elongation factor-2 (EF-2), leading to ADP-ribosyl transferase-mediated apoptosis. (D) Other bacterial toxins, such as toxin A (produced by Clostridium difficile), can induce mitochondria damage and, subsequently, cell death. (E) The cytotoxic necrotizing factor (CNF) is a bacterial single-chain exotoxin produced by Gram-negative bacteria, such as Escherichia coli, and promotes oncogenesis through inducing the activation and proliferation of host cells via a Rho-GTPase-dependent mechanism.

Figure 3

The schematic representation of different types of bacteria-derived chimeric toxins. DT, diphtheria toxin; truncated DTs, DT386 and DT389; STXB, Shiga-like toxin-B; BR2, buforin II; PE, Pseudomonas exotoxin A; PD1, programmed cell death protein-1.

Figure 4

The structure of Pseudomonas exotoxin A (PE) and diphtheria toxin (DT). (A) PE can be manipulated to develop immunotoxins. (B) Structural changes in DT can increase its anticancer activity.