The use of Shiga-like toxin 1 in cancer therapy
Introduction
Ribosome-inactivating proteins such as ricin, abrin, Shiga and Shiga-like toxins represent examples of molecular templates optimized to target and kill eukaryotic cells. They exert their cytotoxic effect on cells by reaching the endoplasmic reticulum (ER) lumen and relocating their toxic domain to the cytosol. The toxicity and lack of selectivity of native toxins towards normal and cancer cells have limited their use as therapeutic agents. Instead, toxin domains have been coupled or fused to targeting agents such as antibodies and cytokines to create guided cytotoxic conjugates. The collective knowledge gathered in the past two decades on the structure and intracellular routing of Shiga toxin and Shiga-like toxin 1, as well as the nature and expression of its receptor on cells, has defined uses for Shiga-like toxin 1 in cancer therapy. This review highlights recent progress in using Shiga-like toxin 1 to target and destroy cancer cells.
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Structure and function of Shiga-like toxin 1
Shiga-like toxin 1 (SLT-1, SLT-I, verotoxin I, VT-I) is a type-II ribosome-inactivating protein produced by pathogenic strains of Escherichia coli. Such strains of SLT-1 producing E. coli (VTEC) are responsible for worldwide outbreaks of hemorrhagic colitis (hamburger disease), hemolytic uremic syndrome (HUS) and thrombocytopenic purpura (TTP) [1], [2], [3]. SLT-1 is a member of a family of protein toxins termed AB5 which assemble into a characteristic quaternary structure composed of a single
Processing and intracellular routing of SLT-1
SLT-1 enters cells by binding to a surface glycolipid called globotriaosylceramide (Galα1-4Galβ1-4glucosylceramide or Gb3), also known as CD77 ([15], [16], [17], [18]; Fig. 2). Once bound, the toxin is internalized via clathrin-coated pits [19], and travels in a retrograde fashion through the Golgi apparatus and the endoplasmic reticulum ([20], [21]; Fig. 3). The importance of the retrograde transport step through the Golgi network was confirmed using Brefeldin A (BFA), an agent that disrupts
Shiga-like toxin 1 as a purging agent
Approximately 50% of patients with intermediate/high grade non-Hodgkin's lymphoma, and virtually all patients with low-grade non-Hodgkin's lymphoma, are not cured by conventional chemotherapy and radiotherapy [34]. High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may represent the best treatment option for patients with acute leukemia in first remission or with intermediate-, high-grade non-Hodgkin's lymphoma in remission [35], [36], [37], [38]. This approach also
In vivo use of Shiga-like toxin 1
CD77 is a cell surface marker expressed on several non-hematopoietic cells such as human enterocytes and human kidney cells. This fact explains why Shiga toxin and SLT-1 represent important virulence factors in the pathogenesis of bacillary dysentery, E. coli infections responsible for hemorrhagic colitis, and hemolytic uremic syndrome. The use of SLT-1 in an in vivo therapeutic setting appears challenging at the present time. Topical application or the local deposition (intratumoral) of the
Future prospects
A purging protocol is presently being devised in preparation for a clinical trial involving patients with multiple myeloma slated to undergo high-dose chemotherapy with stem cell rescue. More importantly, SLT-1 represents an impressive cytotoxic template from which to derive more selective, tumor-targeted toxin variants for in vivo use. Mutant forms of the toxin with altered receptor specificity have now been generated against breast cancer cell lines insensitive to the action of the native
Acknowledgements
Supported by research grants from the Leukemia Society of America and the Terry Fox New Frontiers Initiative
Dr Jean Gariépy is a Professor of Medical Biophysics at the University of Toronto and a Senior Scientist at the Ontario Cancer Institute, Princess Margaret Hospital. He was originally trained as a peptide chemist and NMR spectroscopist in the Department of Biochemistry at the University of Alberta. His postdoctoral training at Stanford University introduced him to the field of bacterial toxins. His research interests have now moved to the areas of drug design, combinatorial chemistry, and
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Dr Jean Gariépy is a Professor of Medical Biophysics at the University of Toronto and a Senior Scientist at the Ontario Cancer Institute, Princess Margaret Hospital. He was originally trained as a peptide chemist and NMR spectroscopist in the Department of Biochemistry at the University of Alberta. His postdoctoral training at Stanford University introduced him to the field of bacterial toxins. His research interests have now moved to the areas of drug design, combinatorial chemistry, and peptide and protein engineering, with the general aim of developing targeted cancer therapies.