AB Toxins as High-Affinity Ligands for Cell Targeting in Cancer Therapy

Abstract

Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show a nanomolar affinity for their target cell receptors, making them an invaluable source of ligands for biomedical applications. Bacterial AB toxins, in particular, are modular proteins that can be genetically engineered to develop high-affinity therapeutic compounds. These toxins consist of two distinct domains: a catalytically active domain and an innocuous domain that acts as a ligand, directing the catalytic domain to the target cells. Interestingly, many tumor cells show receptors on the surface that are recognized by AB toxins, making these high-affinity proteins promising tools for developing new methods for targeting anticancer therapies. Here we describe the structure and mechanisms of action of Diphtheria (Dtx), Anthrax (Atx), Shiga (Stx), and Cholera (Ctx) toxins, and review the potential uses of AB toxins in cancer therapy. We also discuss the main advances in this field, some successful results, and, finally, the possible development of innovative and precise applications in oncology based on engineered recombinant AB toxins.

The Biological Properties of Bacterial Toxins

“…Особенности процесса самосборки субъединиц на мембране клетки-мишени позволяют разделить бинарные токсины на группы: АВ-токсины, A+B-и токсины ABх, 5 Субсемейство маленьких ГТФ-связывающих белков, участвующих в модификации регуляторов актина цитоскелета. 6 Восстановление дисульфидной связи -разрыв ковалентной связи между атомами серы (-S-S-). где x -количество субъединиц B (обычно 2, 5 или 7).…”

“…Обе субъединицы связаны межцепочечной дисульфидной связью. Это связывание через восстановление дисульфидной связи 6 нарушается по пути их проникновения в эндолизосомы, что приводит к высвобождению каталитического домена в цитозоль клетки-мишени. Примерами таких токсинов являются ботулинический (BoNT) и столбнячный (TeNT) нейротоксины; дифтерийный токсин (Dt); рициновый токсин (Rtx) и экзотоксин А псевдомонад [16].…”

Special Issue “Bacterial Toxins and Cancer”

“…The current Special Issue, entitled "Bacterial Toxins and Cancer", collects insightful reviews and research articles on the association between bacterial toxins and cancer initiation and progression, as well as the ability of some bacterial toxins to serve as useful tools for molecular biology studies by manipulating key host cellular processes. Six recent research papers on different topics have been included, specifically three research articles [24][25][26] and three reviews [27][28][29], with over 30 different contributors, that explore recent advances in the field of bacterial toxins and cancer in both the aforementioned areas. In fact, four papers address the potential anti-cancer activity of toxins [24][25][26][27], and two focus on the possible involvement of these virulence factors in cancer initiation and progression [28,29].…”

“…Six recent research papers on different topics have been included, specifically three research articles [24][25][26] and three reviews [27][28][29], with over 30 different contributors, that explore recent advances in the field of bacterial toxins and cancer in both the aforementioned areas. In fact, four papers address the potential anti-cancer activity of toxins [24][25][26][27], and two focus on the possible involvement of these virulence factors in cancer initiation and progression [28,29].…”

“…Marquez-Lopez and Fanarraga [27] propose a review article on the potential uses of bacterial AB toxins in cancer therapy [38]. The authors describe the structure and mechanisms of action of the diphtheria (Dtx) [39], anthrax (Atx) [40], shiga (Stx) [41], and cholera (Ctx) [42] toxins and discuss the potential development of innovative and precise applications in oncology based on engineered recombinant AB toxins.…”