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Toxins
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Toxins and Cancer Therapy
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Toxins and Cancer Therapy

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 31441

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Adam E. Snook

E-Mail Website
Guest Editor
Department of Pharmacology & Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
Interests: guanylyl cyclases; intestinal epithelial cell biology; GI malignancies; colorectal cancer; targeted therapeutics; cancer mucosal antigens; cancer vaccines; immune tolerance; adoptive cell therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Cancer is the second leading cause of death globally and is expected to become an increasing health, social, and economic burden over the coming decades as industrial lifestyles become more prevalent around the world. Approaches to cancer therapy have relied primarily on the selective toxicity of anticancer drugs. Indeed, more than 100 years ago, William Coley, a surgeon at Memorial Hospital in New York, was injecting patients with live bacteria and bacterial products to treat their cancers, often producing remarkable results, especially when treating sarcomas. “Coley’s Toxins” in their original form are no longer used, but the principles Coley began to uncover in the 1890s have evolved into our modern armamentarium for the treatment of cancer. The immunological mechanisms exploited by Coley and uncovered by a century of basic and clinical research have led to the development of remarkable new cancer immunotherapies—between 2015–2018 alone, 46 new cancer immunotherapy indications were approved by the US FDA. Moreover, while Coley’s treatments were often toxic, modern therapies selectively deliver toxic agents to tumors, using targeted radiotherapy, immunotoxins, and nanodelivery systems. Modern approaches even include bacterial enterotoxins, bacteria, and oncolytic viruses to prevent or treat cancer. Together, these therapies are transforming clinical cancer care, but their continued development and new discoveries are needed to ultimately address our growing need for safe and effective cancer therapies over the coming decades.

Keywords

  • Cancer
  • Immunotoxins
  • Immunotherapy
  • Radiotherapy
  • Nanodelivery
  • Bacteria
  • Oncolytic viruses
  • Enterotoxin

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Published Papers (6 papers)

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Editorial

Jump to: Research, Review

5 pages, 226 KiB  
Editorial
Mobilizing Toxins for Cancer Treatment: Historical Perspectives and Current Strategies
by Jessica Kopenhaver, Robert D. Carlson and Adam E. Snook
Toxins 2020, 12(6), 416; https://doi.org/10.3390/toxins12060416 - 23 Jun 2020
Cited by 1 | Viewed by 2402
Abstract
The level of complexity in a disease like cancer presents a number of challenges for effective treatment development, which require significant innovation to overcome [...] Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)

Research

Jump to: Editorial, Review

16 pages, 10596 KiB  
Article
Verotoxin-1-Induced ER Stress Triggers Apoptotic or Survival Pathways in Burkitt Lymphoma Cells
by Justine Debernardi, Catherine Pioche-Durieu, Eric Le Cam, Joëlle Wiels and Aude Robert
Toxins 2020, 12(5), 316; https://doi.org/10.3390/toxins12050316 - 11 May 2020
Cited by 8 | Viewed by 3431
Abstract
Shiga toxins (Stxs) expressed by the enterohaemorrhagic Escherichia coli and enteric Shigella dysenteriae 1 pathogens are protein synthesis inhibitors. Stxs have been shown to induce apoptosis via the activation of extrinsic and intrinsic pathways in many cell types (epithelial, endothelial, and B cells) [...] Read more.
Shiga toxins (Stxs) expressed by the enterohaemorrhagic Escherichia coli and enteric Shigella dysenteriae 1 pathogens are protein synthesis inhibitors. Stxs have been shown to induce apoptosis via the activation of extrinsic and intrinsic pathways in many cell types (epithelial, endothelial, and B cells) but the link between the protein synthesis inhibition and caspase activation is still unclear. Endoplasmic reticulum (ER) stress induced by the inhibition of protein synthesis may be this missing link. Here, we show that the treatment of Burkitt lymphoma (BL) cells with verotoxin-1 (VT-1 or Stx1) consistently induced the ER stress response by activation of IRE1 and ATF6—two ER stress sensors—followed by increased expression of the transcription factor C/REB homologous protein (CHOP). However, our data suggest that, although ER stress is systematically induced by VT-1 in BL cells, its role in cell death appears to be cell specific and can be the opposite: ER stress may enhance VT-1-induced apoptosis through CHOP or play a protective role through ER-phagy, depending on the cell line. Several engineered Stxs are currently under investigation as potential anti-cancer agents. Our results suggest that a better understanding of the signaling pathways induced by Stxs is needed before using them in the clinic. Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)
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14 pages, 2668 KiB  
Article
Cnf1 Variants Endowed with the Ability to Cross the Blood–Brain Barrier: A New Potential Therapeutic Strategy for Glioblastoma
by Andrea Colarusso, Zaira Maroccia, Ermenegilda Parrilli, Elena Angela Pia Germinario, Andrea Fortuna, Stefano Loizzo, Laura Ricceri, Maria Luisa Tutino, Carla Fiorentini and Alessia Fabbri
Toxins 2020, 12(5), 291; https://doi.org/10.3390/toxins12050291 - 4 May 2020
Cited by 8 | Viewed by 2831
Abstract
Among gliomas, primary tumors originating from glial cells, glioblastoma (GBM) identified as WHO grade IV glioma, is the most common and aggressive malignant brain tumor. We have previously shown that the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) is remarkably effective [...] Read more.
Among gliomas, primary tumors originating from glial cells, glioblastoma (GBM) identified as WHO grade IV glioma, is the most common and aggressive malignant brain tumor. We have previously shown that the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) is remarkably effective as an anti-neoplastic agent in a mouse model of glioma, reducing the tumor volume, increasing survival, and maintaining the functional properties of peritumoral neurons. However, being unable to cross the blood–brain barrier (BBB), CNF1 requires injection directly into the brain, which is a very invasive administration route. Thus, to overcome this pitfall, we designed a CNF1 variant characterized by the presence of an N-terminal BBB-crossing tag. The variant was produced and we verified whether its activity was comparable to that of wild-type CNF1 in GBM cells. We investigated the signaling pathways engaged in the cell response to CNF1 variants to provide preliminary data to the subsequent studies in experimental animals. CNF1 may represent a novel avenue for GBM therapy, particularly because, besides blocking tumor growth, it also preserves the healthy surrounding tissue, maintaining its architecture and functionality. This renders CNF1 the most interesting candidate for the treatment of brain tumors, among other potentially effective bacterial toxins. Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)
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20 pages, 2654 KiB  
Article
Inclusion of a Furin Cleavage Site Enhances Antitumor Efficacy against Colorectal Cancer Cells of Ribotoxin α-Sarcin- or RNase T1-Based Immunotoxins
by Javier Ruiz-de-la-Herrán, Jaime Tomé-Amat, Rodrigo Lázaro-Gorines, José G. Gavilanes and Javier Lacadena
Toxins 2019, 11(10), 593; https://doi.org/10.3390/toxins11100593 - 12 Oct 2019
Cited by 10 | Viewed by 5184
Abstract
Immunotoxins are chimeric molecules that combine the specificity of an antibody to recognize and bind tumor antigens with the potency of the enzymatic activity of a toxin, thus, promoting the death of target cells. Among them, RNases-based immunotoxins have arisen as promising antitumor [...] Read more.
Immunotoxins are chimeric molecules that combine the specificity of an antibody to recognize and bind tumor antigens with the potency of the enzymatic activity of a toxin, thus, promoting the death of target cells. Among them, RNases-based immunotoxins have arisen as promising antitumor therapeutic agents. In this work, we describe the production and purification of two new immunoconjugates, based on RNase T1 and the fungal ribotoxin α-sarcin, with optimized properties for tumor treatment due to the inclusion of a furin cleavage site. Circular dichroism spectroscopy, ribonucleolytic activity studies, flow cytometry, fluorescence microscopy, and cell viability assays were carried out for structural and in vitro functional characterization. Our results confirm the enhanced antitumor efficiency showed by these furin-immunotoxin variants as a result of an improved release of their toxic domain to the cytosol, favoring the accessibility of both ribonucleases to their substrates. Overall, these results represent a step forward in the design of immunotoxins with optimized properties for potential therapeutic application in vivo. Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)
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Review

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23 pages, 1344 KiB  
Review
Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy
by Robert D. Carlson, John C. Flickinger, Jr. and Adam E. Snook
Toxins 2020, 12(4), 241; https://doi.org/10.3390/toxins12040241 - 9 Apr 2020
Cited by 53 | Viewed by 9220
Abstract
The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding [...] Read more.
The ability of the immune system to precisely target and eliminate aberrant or infected cells has long been studied in the field of infectious diseases. Attempts to define and exploit these potent immunological processes in the fight against cancer has been a longstanding effort dating back over 100 years to when Dr. William Coley purposefully infected cancer patients with a cocktail of heat-killed bacteria to stimulate anti-cancer immune processes. Although the field of cancer immunotherapy has been dotted with skepticism at times, the success of immune checkpoint inhibitors and recent FDA approvals of autologous cell therapies have pivoted immunotherapy to center stage as one of the most promising strategies to treat cancer. This review aims to summarize historic milestones throughout the field of cancer immunotherapy as well as highlight current and promising immunotherapies in development. Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)
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14 pages, 820 KiB  
Review
Botulinum Neurotoxins and Cancer—A Review of the Literature
by Shivam O. Mittal and Bahman Jabbari
Toxins 2020, 12(1), 32; https://doi.org/10.3390/toxins12010032 - 5 Jan 2020
Cited by 28 | Viewed by 6870
Abstract
Botulinum neurotoxins (BoNT) possess an analgesic effect through several mechanisms including an inhibition of acetylcholine release from the neuromuscular junction as well as an inhibition of specific pain transmitters and mediators. Animal studies have shown that a peripheral injection of BoNTs impairs the [...] Read more.
Botulinum neurotoxins (BoNT) possess an analgesic effect through several mechanisms including an inhibition of acetylcholine release from the neuromuscular junction as well as an inhibition of specific pain transmitters and mediators. Animal studies have shown that a peripheral injection of BoNTs impairs the release of major pain transmitters such as substance P, calcitonin gene related peptide (CGRP) and glutamate from peripheral nerve endings as well as peripheral and central neurons (dorsal root ganglia and spinal cord). These effects lead to pain relief via the reduction of peripheral and central sensitization both of which reflect important mechanisms of pain chronicity. This review provides updated information about the effect of botulinum toxin injection on local pain caused by cancer, painful muscle spasms from a remote cancer, and pain at the site of cancer surgery and radiation. The data from the literature suggests that the local injection of BoNTs improves muscle spasms caused by cancerous mass lesions and alleviates the post-operative neuropathic pain at the site of surgery and radiation. It also helps repair the parotid damage (fistula, sialocele) caused by facial surgery and radiation and improves post-parotidectomy gustatory hyperhidrosis. The limited literature that suggests adding botulinum toxins to cell culture slows/halts the growth of certain cancer cells is also reviewed and discussed. Full article
(This article belongs to the Special Issue Toxins and Cancer Therapy)
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