# Bacterial Therapy of Cancer: A Way to the Dustbin of History or to the Medicine of the Future?
## 5 Bacteria in Cancer Therapy
### Mechanisms of Antitumor Action
#### 5.2.2 Production of the Cell-Death-Inducing Agents  
There is a wide range of bacterial-derived products which can specifically target the cancer cells and exert a cytotoxic effect. Among the cytotoxic agents are bacterial toxins, enzymes, peptides, and some secondary bacterial metabolites. _<Bacterial Toxins>_. Bacteria express and release some toxins that can be cytotoxic or, at lower concentrations, may result in the alteration of proliferation, differentiation, and apoptosis. Some of them are able to effectively inhibit tumor growth through cell-cycle arrest,tumor cell signal pathway interruption, and other mechanisms. One of the well-known antitumor agent bacterial toxins is cytolysin CyA. Cytolysins are pore-forming agents that generate multimeric pores in the cell membrane and contribute to cell destruction. Cytolysins are generally derived from _Escherichia coli_, _Staphylococcus aureus_[96], or _Salmonella typhimurium_[97; 98]. Actually, mice treated with _S. typhimurium_ or _E. coli_ strains expressing the CyA toxin demonstrated tumor-growth inhibition [98; 99]. Another well-known toxin is the diphtheia toxin (DT), which is a main virulence factor produced by _Corynebacterium diphtheria_. At low concentrations, this toxin has lethal activity on mammalian cells. Modified DT-based toxins have proved effective in the treatment of several types of cancers [100; 101]. _Clostrium difficile_ toxin includes two subtypes of cytotoxin and enterotoxin which can kill cancer cells by recruiting proinflammatory factors to activate the immune response [89]. _Clostrium botulinum_ produces botulinum neurotoxin A, which reduces cell growth and proliferation in prostate cancer lines PC-3 and LNCaP [102], and induces apoptosis in breast cancer cell lines T47D [103; 104]. Enterotoxin produced by _Clostridium perfringens_ also has anticancer activity, which leads to dose-dependent acute toxicity by binding to the overexpressed claudin-4 receptor on pancreatic cancer cells [105]. Verotoxin 1 (VT-1), mostly recognized as Shiga toxin-1 (Stx1), is produced by pathogenic _E. coli_ and can stop the cell cycle in the HCT116 cell line of colon cancer [106; 107]. Exotoxin (PE) synthesized by _Pseudomonas aeruginosa_ inhibits protein synthesis through ADP ribosylation, leading to cancer cell apoptosis [107; 108]. _<Bacterial Enzymes_> Bacteria produce a wide array of enzymes. Some of them can act on the essential amino acids required for tumor growth. One of the commonly investigated bacterial enzymes is L-asparaginase, an enzyme produced by _Escherichia coli_, _Bacillus subtilis_, Streptomyces, or Erwinia species [67]. This enzyme catalyzes the hydrolysis of asparagine, reducing its blood concentration and causing processes that are fatal to tumor cells [109]. L-asparaginase has been proven effective in the treatment of acute lymphoblastic leukemia, lymphomasarcoma, neoplasia, and other malignancies [109; 110; 111]. Other bacterial enzymes of interest are arginine deaminase and arginine decarboxylase, which are involved in arginine catabolism [112]. It was demonstrated that arginine deaminase produced from _Streptococcus pyogenes_ can consume arginine in tumor cells, resulting in decreased proliferation of arginine-deficient tumor glioblastoma multiforme [113]. _<Bacterioins_> Bacteria produce a broad spectrum of ribosomal synthesized proteinaceous and peptide toxins--bacterioins. These bacterial antimicrobial peptides are mainly directed against closely related bacterial species in the same niche. In some cases, bacteriocins can also inhibit the growth of tumor cells. The cationic charge and amphiphilic nature allow the bacteriocin to interact with the negatively charged cell membrane and destroy the membrane integrity, triggering the apoptosis of the cancer cells [114].