Bacterial Toxins for Cancer Therapy

Abstract

Several pathogenic bacteria secrete toxins to inhibit the immune system of the infected organism. Frequently, they catalyze a covalent modification of specific proteins. Thereby, they block production and/or secretion of antibodies or cytokines. Moreover, they disable migration of macrophages and disturb the barrier function of epithelia. In most cases, these toxins are extremely effective enzymes with high specificity towards their cellular substrates, which are often central signaling molecules. Moreover, they encompass the capacity to enter mammalian cells and to modify their substrates in the cytosol. A few molecules, at least of some toxins, are sufficient to change the cellular morphology and function of a cell or even kill a cell. Since many of those toxins are well studied concerning molecular mechanisms, cellular receptors, uptake routes, and structures, they are now widely used to analyze or to influence specific signaling pathways of mammalian cells. Here, we review the development of immunotoxins and targeted toxins for the treatment of a disease that is still hard to treat: cancer.

Bacterial Toxins and Targeted Brain Therapy: New Insights from Cytotoxic Necrotizing Factor 1 (CNF1)

“…For example, it has been discovered that the selective activation of RhoA/B/C by Yersinia cytotoxic necrotizing factor (CNFy) can stimulate the apoptotic pathway in specific tumor cells in which CNF1 has no effect [ 48 ]. Another alternative could be represented by immunotoxins, in order to precisely select the target cells through the specificity of an antibody [ 13 , 68 ]. Therefore, the use of more selective toxins might be a feasible new avenue for tumor treatments.…”

“…In this framework, toxins represent a promising tool for GBM therapy because of their features in terms of specificity and biological action. In particular, (i) toxins are extremely potent and not subjected to mechanisms of drug resistance; (ii) the active core of the toxins can be isolated and cloned becoming small in molecular size, and thus more efficient to penetrate into solid tumors; (iii) toxins can be combined by recombinant DNA technology with selective carriers or antibodies (Abs) against surface receptors, thus allowing specific entry of the catalytic toxin domain into selected tumor cell types [ 13 ].…”

Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer

“…Many bacterial toxins have been extensively studied for their promising clinical applications [47][48][49][50][51]. A previous study has shown that human gingival squamous carcinoma cell line Ca9-22 transfected with Actinobacillus actinomycetemcomitans-CdtB-expressing plasmid manifested G2 phase arrest and cell growth inhibition [52].…”

Principles of Immunotherapy: Implications for Treatment Strategies in Cancer and Infectious Diseases

“…The IL-2 moiety allows for selective targeting of IL-2R bearing cells. Upon IL-2 and IL-2R binding, the fusion protein is internalized and transported to the cell cytosol where the catalytic domain inhibits protein synthesis resulting in downstream alterations that ultimately lead to apoptosis (Zahaf and Schmidt, 2017). DD has been approved for treatment of cutaneous T cell lymphoma and subsequent human studies.…”