Shiga Toxins as Antitumor Tools

Abstract

Shiga toxins (Stxs), also known as Shiga-like toxins (SLT) or verotoxins (VT), constitute a family of structurally and functionally related cytotoxic proteins produced by the enteric pathogens Shigella dysenteriae type 1 and Stx-producing Escherichia coli (STEC). Infection with these bacteria causes bloody diarrhea and other pathological manifestations that can lead to HUS (hemolytic and uremic syndrome). At the cellular level, Stxs bind to the cellular receptor Gb3 and inhibit protein synthesis by removing an adenine from the 28S rRNA. This triggers multiple cellular signaling pathways, including the ribotoxic stress response (RSR), unfolded protein response (UPR), autophagy and apoptosis. Stxs cause several pathologies of major public health concern, but their specific targeting of host cells and efficient delivery to the cytosol could potentially be exploited for biomedical purposes. Moreover, high levels of expression have been reported for the Stxs receptor, Gb3/CD77, in Burkitt’s lymphoma (BL) cells and on various types of solid tumors. These properties have led to many attempts to develop Stxs as tools for biomedical applications, such as cancer treatment or imaging, and several engineered Stxs are currently being tested. We provide here an overview of these studies.

Enterohemorrhagic Escherichia coli and a Fresh View on Shiga Toxin-Binding Glycosphingolipids of Primary Human Kidney and Colon Epithelial Cells and Their Toxin Susceptibility

“…In recent years, a variety of alternative treatment approaches and therapeutic interventions has been developed and evaluated in vitro, in animal models and clinical trials for preventing EHEC-associated HUS [297,298]. The majority of possible non-antibiotic therapeutics has been or is in the developmental stage aimed to neutralize Stx, to prevent toxin adhesion, to block receptor biosynthesis, and to interfere trafficking, processing, and activity of the toxin within the cell [6,156,293,[299][300][301]. Since Stx induces the secretion of inflammatory cytokines and chemokines from susceptible cells that contribute to the pathogenesis of HUS, these compounds are useful indicators of disease activity as well as predictors of disease progression and candidates for an anti-inflammation therapy as an additional treatment regimen for severe E. coli-associated HUS [302].…”

“…This strategy offers a potential new candidate for a preventive antimicrobial for EHEC infections [345,346]. The retrograde transport of internalized Stx directly from early endosomes to the Golgi apparatus is an essential step to bypass degradation in the late endosomes and lysosomes, which then continues to the endoplasmic reticulum before translocation of the enzymatically active moiety to the ribosomal target in the cytosol [167,301,309,[347][348][349][350]. This renders the crucial retrograde transportation route an ideal attack point for small molecule inhibitors of toxin trafficking as possible therapeutics acting at the endosome/Golgi interface [351,352].…”

Bacteria-derived chimeric toxins as potential anticancer agents

“…Considering the low remedial index of available cytotoxic drugs and the capacity of cancer cells to become resistant to these manufactured medications, it is essential to develop novel treatments for aggressive malignancies ( 7 ). Constructing chimeric bacterial toxins conjugated with cytotoxic agents via genetic engineering can help improve the anticancer properties of these compounds ( 72 ). In this regard, bacterial toxins may be combined with either immunomodulators or chemotherapeutics ( 7 ).…”

“…In this regard, bacterial toxins may be combined with either immunomodulators or chemotherapeutics ( 7 ). The B-subunit of Shiga-like toxin (STXB) has been shown to present anticancer effects via inducing apoptosis and inhibiting cell cycle progression ( 72 ). Other studies have also shown that ST, via binding to specific surface receptors, can be an effective transporter for delivering toxic proteins to cells.…”

“…The conjugation of a molecule to ST can change the toxin’s properties such as stability and immunogenicity and enhance its toxic effects. In addition, ST is relatively small, and pairing it with larger molecules can improve its binding efficacy to globotriaosylceramide 3 (GB3) ( 8 , 72 ), a functional alternative receptor for ST. The overexpression of GB3 on the surface of malignant cells has been reported in primary breast cancer, ovarian cancer, gastric adenocarcinoma, and acute nonlymphocytic leukemia ( 72 ).…”