Cytotoxic Mechanisms of Ribosome-Inactivating Proteins and Related Immunotoxins

A special issue of Stresses (ISSN 2673-7140). This special issue belongs to the section "Animal and Human Stresses".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 2323

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Department of Medical and Surgical Sciences-DIMEC, General Pathology Section, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy
Interests: Xanthine oxidoreductase; oxidative stress; uric acid; nitric oxide; cytotoxicity; plant toxin; rRNA glycosylase; immunotoxin; targeted therapy; anti-tumour therapy
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Dear Colleagues,

Ribosome-inactivating proteins (RIPs) are toxic plant enzymes with rRNA N-glycosylase activity that can remove a specific adenine residue from 28S rRNA, thus causing the irreversible inhibition of protein synthesis and cell death. In addition, some authors have reported that RIPs are able to deadenylate several other substrates such as poly(A), mRNA, tRNA, and DNA, thus displaying polynucleotide:adenine glycosylase activity.

For many years, rRNA deadenylation was thought to be the only enzymatic activity of RIPs, and ribosome inactivation was considered the pivotal event in cell death triggering. Apoptotic changes in cells intoxicated with ricin or abrin were firstly described in 1987, and subsequently, apoptosis was commonly considered the typical mode of RIP-induced cell death. However, several lines of experimental evidence demonstrate that RIP intoxication can induce multiple cell death pathways, involving at least apoptosis, necroptosis and autophagy. Moreover, it is now evident that RIPs can induce apoptosis regardless of protein synthesis inhibition. Despite the progress made in the knowledge of the pathogenetic mechanisms of these molecules, many points still need to be clarified. Among these are the primary molecular events induced by RIP intoxication, the correlation between the cell differentiation degree and RIP sensitivity, the interconnection between different cell death pathways, and the timing of all these events.

RIPs have been used in many experimental strategies in medicine, in order to specifically destroy cells responsible for pathological conditions. These plant toxins have been tested as native molecules, in locoregional treatments, or as toxic components of immunotoxins for experimental therapy in several pathologies, ranging from cancer and pain control to autoimmune diseases and transplant rejection. The elucidation of the molecular details of cell intoxication by RIP is a fundamental requirement for building increasingly effective immunotoxins and predicting, in part, their possible side effects.

The aim of this Special Issue is to collect original articles, reviews and short communications that provide readers with a comprehensive and clear overview of the cell stress mechanisms and death pathways induced by RIPs.

Dr. Andrea Bolognesi
Guest Editor

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Keywords

  • plant toxins
  • lectins
  • ribosome-inactivating proteins (RIP)
  • rRNA N-glycosylases
  • polynucleotide:adenosine glycosidase
  • immunotoxins
  • immunotargeting
  • apoptosis
  • necroptosis
  • ribotoxic stress
  • oxidative stress
  • unfolded protein response
  • signal transduction

Published Papers (1 paper)

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12 pages, 2140 KiB  
Article
Plant Toxins as Potential Alternatives to Botulinum Toxin for Eye-Movement Disorder Therapy
by Massimo Bortolotti, Andrea Zanello, Lorenzo Serra, Francesco Biscotti, Letizia Polito and Andrea Bolognesi
Stresses 2023, 3(1), 270-281; https://doi.org/10.3390/stresses3010020 - 1 Feb 2023
Cited by 2 | Viewed by 1605
Abstract
The most successful alternative to traditional surgery for ocular muscle spasm treatment is the intramuscular injection of botulinum toxin (BTX), which allows the maintenance of the muscle dynamics and the absence of scars. However, the main BTX disadvantage is its nonpermanent effect. A [...] Read more.
The most successful alternative to traditional surgery for ocular muscle spasm treatment is the intramuscular injection of botulinum toxin (BTX), which allows the maintenance of the muscle dynamics and the absence of scars. However, the main BTX disadvantage is its nonpermanent effect. A possible way for overcoming this obstacle could be represented by the enzymatic surgery using plant toxins known as ribosome-inactivating proteins (RIPs). In this paper, two highly toxic RIPs, namely, ricin and stenodactylin, were considered in a preliminary study for their possible use in the treatment of strabismus and oculofacial dystonias, as alternatives to BTX. Both RIPs showed a strong cytotoxic effect against rhabdomyosarcoma cell lines and myotube differentiated cells, with stenodactylin being about 10-fold more toxic than ricin. Moreover, stenodactylin showed a much higher cytotoxicity on myoblasts than on rhabdomyosarcoma cells. In our experimental conditions, stenodactylin did not damage conjunctival cells. Despite the limitations due to in vitro experiments, our data show that the high cytotoxicity of stenodactylin allows the use of a very low dose and, consequently, of very low injection volumes. This can represent a great advantage in the case of in vivo locoregional treatment. Furthermore, it is possible to modulate the chemoablation of myocytes while destroying myoblasts, thus reducing regenerative phenomena. The risk of cytotoxicity to surrounding tissues would be strongly reduced by the low injected volume and the relative resistance of conjunctival cells. In conclusion, our data suggest that stenodactylin and ricin could represent potential candidates to substitute BTX in ocular dystonia therapy. Full article
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