E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Special Issue "Toxins as Therapeutics"

Quicklinks

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (15 September 2010)

Special Issue Editor

Guest Editor
Prof. Dr. Richard J. Lewis (Website)

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia
Fax: +61 7 3346 2101
Interests: cone snail and spider venom peptides; sodium and calcium channels; nAChRs; monoamine transporters; adrenoceptors; ciguatera and ciguatoxins; pain; toxin SAR

Special Issue Information

Dear Colleagues,

Natural products lethal to animals (toxins) provide a rich source of leads for new therapeutics for diseases that range from cancer to diabetes to pain. This special issue on "Toxins as Therapeutics" focuses on toxins and toxin inspired leads, including the emergence of venoms as an underutilized source of highly evolved bioactive peptides, that have clinical potential.

Prof. Dr. Richard J. Lewis
Guest Editor

Keywords

  • calcium channels
  • acetylcholine receptors
  • sodium channels
  • potassium channels
  • chloride ion channels
  • TRP channels
  • NMDA receptor
  • ASIC channels
  • monoamine transporters
  • opiate receptors
  • GLP-1 receptors
  • neurotensin receptor
  • antibiotics
  • botulinum toxins
  • cone snail venom peptides
  • spider venom peptides
  • sea anemone toxins
  • scorpion toxins
  • snake toxins

Published Papers (17 papers)

View options order results:
result details:
Displaying articles 1-17
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle In Vitro Antiplasmodial Activity of Phospholipases A2 and a Phospholipase Homologue Isolated from the Venom of the Snake Bothrops asper
Toxins 2012, 4(12), 1500-1516; doi:10.3390/toxins4121500
Received: 2 November 2012 / Revised: 23 November 2012 / Accepted: 30 November 2012 / Published: 14 December 2012
Cited by 4 | PDF Full-text (1639 KB) | HTML Full-text | XML Full-text
Abstract
The antimicrobial and antiparasite activity of phospholipase A2 (PLA2) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: [...] Read more.
The antimicrobial and antiparasite activity of phospholipase A2 (PLA2) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: one containing catalytically-active phospholipases A2 (PLA2) (fraction V) and another containing a PLA2 homologue devoid of enzymatic activity (fraction VI). The antiplasmodial effect was assessed on in vitro cultures of Plasmodium falciparum. The whole venom of B. asper, as well as its fractions V and VI, were active against the parasite at 0.13 ± 0.01 µg/mL, 1.42 ± 0.56 µg/mL and 22.89 ± 1.22 µg/mL, respectively. Differences in the cytotoxic activity on peripheral blood mononuclear cells between the whole venom and fractions V and VI were observed, fraction V showing higher toxicity than total venom and fraction VI. Regarding toxicity in mice, the whole venom showed the highest lethal effect in comparison to fractions V and VI. These results suggest that B. asper PLA2 and its homologue have antiplasmodial potential. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessArticle The Discodermia calyx Toxin Calyculin A Enhances Cyclin D1 Phosphorylation and Degradation, and Arrests Cell Cycle Progression in Human Breast Cancer Cells
Toxins 2011, 3(1), 105-119; doi:10.3390/toxins3010105
Received: 8 October 2010 / Revised: 8 January 2011 / Accepted: 21 January 2011 / Published: 24 January 2011
Cited by 4 | PDF Full-text (541 KB) | HTML Full-text | XML Full-text
Abstract
Cyclin D1 is a key regulator of the cell cycle that is over expressed in more than half of breast cancer patients. The levels of cyclin D1 are controlled primarily through post-translational mechanisms and phosphorylation of cyclin D1 at T286 induces its [...] Read more.
Cyclin D1 is a key regulator of the cell cycle that is over expressed in more than half of breast cancer patients. The levels of cyclin D1 are controlled primarily through post-translational mechanisms and phosphorylation of cyclin D1 at T286 induces its proteasomal degradation. To date, no studies have explored the involvement of phosphatases in this process. Here we treated human breast cancer cells with the structurally distinct toxins calyculin A, okadaic acid, and cantharidin, which are known to inhibit Ser/Thr phosphatases of the PPP family. At low nanomolar concentrations calyculin A induced T286 phosphorylation and degradation of cyclin D1 via the proteosome in MDA-MB-468 and MDA-MB-231 cells. Cyclin D1 degradation also was dose-dependently induced by okadaic acid and catharidin, implicating a negative regulatory role for type-2A phosphatases. These effects occurred without increasing phosphorylation of p70S6K, cyclin D3, or myosin light chain that were used as endogenous reporters of cellular PP2A and PP1 activity. A reverse phase phosphoprotein array analysis revealed increased phosphorylation of only 6 out of 33 Ser/Thr phosphosites, indicating selective inhibition of phosphatases by calyculin A. Calyculin A treatment induced cell cycle arrest in MDA-MB-468 and MCF-7 breast cancer cells. These findings suggest that a specific pool of type-2A phosphatase is inhibited by calyculin A leading to the degradation of cyclin D1 in human breast cancer cells. The results highlight the utility of toxins as pharmacological probes and points to the T286 cyclin D1 phosphatase inhibited by calyculin A as a possible target for chemotherapy to treat triple negative breast cancer. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessArticle Strategy for Treating Motor Neuron Diseases Using a Fusion Protein of Botulinum Toxin Binding Domain and Streptavidin for Viral Vector Access: Work in Progress
Toxins 2010, 2(12), 2872-2889; doi:10.3390/toxins2122872
Received: 11 October 2010 / Revised: 16 December 2010 / Accepted: 17 December 2010 / Published: 20 December 2010
Cited by 2 | PDF Full-text (644 KB) | HTML Full-text | XML Full-text
Abstract
Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on [...] Read more.
Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on the specificity of botulinum toxin, to direct entry of viral vectors carrying candidate therapeutic genes into motor neurons. We have engineered and expressed fusion proteins consisting of the binding domain of botulinum toxin type A fused to streptavidin (SAv). This fusion protein will direct biotinylated viral vectors carrying therapeutic genes into motor nerve terminals where they can enter the acidified endosomal compartments, be released and undergo retrograde transport, to deliver the genes to motor neurons. Both ends of the fusion proteins are shown to be functionally intact. The binding domain end binds to mammalian nerve terminals at neuromuscular junctions, ganglioside GT1b (a target of botulinum toxin), and a variety of neuronal cells including primary chick embryo motor neurons, N2A neuroblastoma cells, NG108-15 cells, but not to NG CR72 cells, which lack complex gangliosides. The streptavidin end binds to biotin, and to a biotinylated Alexa 488 fluorescent tag. Further studies are in progress to evaluate the delivery of genes to motor neurons in vivo, by the use of biotinylated viral vectors. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessArticle Novel Cytotoxic Vectors Based on Adeno-Associated Virus
Toxins 2010, 2(12), 2754-2768; doi:10.3390/toxins2122754
Received: 11 November 2010 / Revised: 29 November 2010 / Accepted: 30 November 2010 / Published: 1 December 2010
Cited by 5 | PDF Full-text (610 KB) | HTML Full-text | XML Full-text
Abstract
Vectors based on adeno-associated virus (AAV) are promising tools for gene therapy. The production of strongly toxic vectors, for example for cancer-directed gene transfer, is often unfeasible due to uncontrolled expression of toxic genes in vector-producing cells. Using an approach based on [...] Read more.
Vectors based on adeno-associated virus (AAV) are promising tools for gene therapy. The production of strongly toxic vectors, for example for cancer-directed gene transfer, is often unfeasible due to uncontrolled expression of toxic genes in vector-producing cells. Using an approach based on transcriptional repression, we have created novel AAV vectors carrying the genes coding for diphtheria toxin A (DTA) and the pro-apoptotic PUMA protein. The DTA vector had a significant toxic effect on a panel of tumor cell lines, and abrogation of protein synthesis could be shown. The PUMA vector had a toxic effect on HeLa and RPMI 8226 cells, and sensitized transduced cells to doxorubicin. To permit targeted gene transfer, we incorporated the DTA gene into a genetically modified AAV-2 capsid previously developed by our group that mediates enhanced transduction of murine breast cancer cells in vitro. This vector had a stronger cytotoxic effect on breast cancer cells than DTA vectors with wildtype AAV capsid or vectors with a random capsid modification. The vector production and application system presented here allows for easy exchange of promotors, transgenes and capsid specificity for certain target cells. It will therefore be of great possible value in a broad range of applications in cytotoxic gene therapy and significantly broadens the spectrum of available tools for AAV-based gene therapy. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessArticle SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model
Toxins 2010, 2(9), 2242-2257; doi:10.3390/toxins2092242
Received: 23 July 2010 / Revised: 20 August 2010 / Accepted: 26 August 2010 / Published: 27 August 2010
PDF Full-text (873 KB) | HTML Full-text | XML Full-text
Abstract
SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models [...] Read more.
SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessArticle Characterization of SNARE Cleavage Products Generated by Formulated Botulinum Neurotoxin Type-A Drug Products
Toxins 2010, 2(8), 2198-2212; doi:10.3390/toxins2082198
Received: 9 July 2010 / Revised: 10 July 2010 / Accepted: 18 August 2010 / Published: 19 August 2010
Cited by 9 | PDF Full-text (179 KB) | HTML Full-text | XML Full-text
Abstract
The study evaluated substrate cleavage product(s) generated by three botulinum neurotoxin serotype A (BoNT/A) medicinal drug products utilizing a novel and highly specific, light-chain activity, high-performance liquid chromatography (LCA-HPLC) method. Samples were reacted with a commercially available BoNT/A fluorescent substrate derived from [...] Read more.
The study evaluated substrate cleavage product(s) generated by three botulinum neurotoxin serotype A (BoNT/A) medicinal drug products utilizing a novel and highly specific, light-chain activity, high-performance liquid chromatography (LCA-HPLC) method. Samples were reacted with a commercially available BoNT/A fluorescent substrate derived from the SNAP-25 sequence. Reaction products were separated by reversed-phase HPLC. The method detected an atypical cleavage pattern by one of the formulated drug products. IncobotulinumtoxinA produced two cleavage fragments rather than the single fragment typically generated by BoNT/A. Identification confirmed the secondary cleavage at a position corresponding to SNAP-25 Arg198–Ala199 (normal BoNT/A cleavage is Gln197–Arg198). Arg198–Ala199 is also the cleavage site for trypsin and serotype C toxin. Normal cleavage was observed for all other BoNT/A drug product samples, as well as 900-kD and 150-kD bulk toxin BoNT/A. The reason for this unexpected secondary cleavage pattern by one formulated BoNT/A drug product is unknown. Possible explanations include a contaminating protease and/or damage to the 150-kD type-A toxin causing nonspecific substrate recognition and subsequent cleavage uncharacteristic of type-A toxin. The BoNT/A drug products were also analyzed via the LCA-HPLC assay using a commercial BoNT/C fluorescent substrate derived from the syntaxin sequence. Cleavage of the serotype C substrate by incobotulinumtoxinA was also confirmed whilst neither of the other drug products cleaved the syntaxin substrate. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)

Review

Jump to: Research

Open AccessReview From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules
Toxins 2011, 3(3), 260-293; doi:10.3390/toxins3030260
Received: 8 November 2010 / Revised: 1 February 2011 / Accepted: 16 March 2011 / Published: 21 March 2011
Cited by 8 | PDF Full-text (1431 KB) | HTML Full-text | XML Full-text
Abstract
Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found [...] Read more.
Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Towards New Uses of Botulinum Toxin as a Novel Therapeutic Tool
Toxins 2011, 3(1), 63-81; doi:10.3390/toxins3010063
Received: 7 December 2010 / Revised: 3 January 2011 / Accepted: 4 January 2011 / Published: 12 January 2011
Cited by 22 | PDF Full-text (535 KB) | HTML Full-text | XML Full-text
Abstract
The uses of botulinum toxin in the fields of neurology, ophthalmology, urology, rehabilitation medicine and aesthetic applications have been revolutionary for the treatment of patients. This non-invasive therapeutic has continually been developed since first discovered in the 1970s as a new approach [...] Read more.
The uses of botulinum toxin in the fields of neurology, ophthalmology, urology, rehabilitation medicine and aesthetic applications have been revolutionary for the treatment of patients. This non-invasive therapeutic has continually been developed since first discovered in the 1970s as a new approach to what were previously surgical treatments. As these applications develop, so also the molecules are developing into tools with new therapeutic properties in specific clinical areas. This review examines how the botulinum toxin molecule is being adapted to new therapeutic uses and also how new areas of use for the existing molecules are being identified. Prospects for future developments are also considered. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Botulinum Neurotoxin for Pain Management: Insights from Animal Models
Toxins 2010, 2(12), 2890-2913; doi:10.3390/toxins2122890
Received: 18 November 2010 / Revised: 17 December 2010 / Accepted: 20 December 2010 / Published: 21 December 2010
Cited by 29 | PDF Full-text (712 KB) | HTML Full-text | XML Full-text
Abstract
The action of botulinum neurotoxins (BoNTs) at the neuromuscular junction has been extensively investigated and knowledge gained in this field laid the foundation for the use of BoNTs in human pathologies characterized by excessive muscle contractions. Although much more is known about [...] Read more.
The action of botulinum neurotoxins (BoNTs) at the neuromuscular junction has been extensively investigated and knowledge gained in this field laid the foundation for the use of BoNTs in human pathologies characterized by excessive muscle contractions. Although much more is known about the action of BoNTs on the peripheral system, growing evidence has demonstrated several effects also at the central level. Pain conditions, with special regard to neuropathic and intractable pain, are some of the pathological states that have been recently treated with BoNTs with beneficial effects. The knowledge of the action and potentiality of BoNTs utilization against pain, with emphasis for its possible use in modulation and alleviation of chronic pain, still represents an outstanding challenge for experimental research. This review highlights recent findings on the effects of BoNTs in animal pain models. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessReview Spider-Venom Peptides as Therapeutics
Toxins 2010, 2(12), 2851-2871; doi:10.3390/toxins2122851
Received: 16 November 2010 / Revised: 17 December 2010 / Accepted: 17 December 2010 / Published: 20 December 2010
Cited by 80 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
Abstract
Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider [...] Read more.
Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessReview Targeted Secretion Inhibitors—Innovative Protein Therapeutics
Toxins 2010, 2(12), 2795-2815; doi:10.3390/toxins2122795
Received: 15 October 2010 / Revised: 16 November 2010 / Accepted: 2 December 2010 / Published: 3 December 2010
Cited by 17 | PDF Full-text (260 KB) | HTML Full-text | XML Full-text
Abstract
Botulinum neurotoxins are highly effective therapeutic products. Their therapeutic success results from highly specific and potent inhibition of neurotransmitter release with a duration of action measured in months. These same properties, however, make the botulinum neurotoxins the most potent acute lethal toxins [...] Read more.
Botulinum neurotoxins are highly effective therapeutic products. Their therapeutic success results from highly specific and potent inhibition of neurotransmitter release with a duration of action measured in months. These same properties, however, make the botulinum neurotoxins the most potent acute lethal toxins known. Their toxicity and restricted target cell activity severely limits their clinical utility. Understanding the structure-function relationship of the neurotoxins has enabled the development of recombinant proteins selectively incorporating specific aspects of their pharmacology. The resulting proteins are not neurotoxins, but a new class of biopharmaceuticals, Targeted Secretion Inhibitors (TSI), suitable for the treatment of a wide range of diseases where secretion plays a major role. TSI proteins inhibit secretion for a prolonged period following a single application, making them particularly suited to the treatment of chronic diseases. A TSI for the treatment of chronic pain is in clinical development. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessReview Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack
Toxins 2010, 2(11), 2699-2737; doi:10.3390/toxins2112699
Received: 20 October 2010 / Revised: 29 October 2010 / Accepted: 4 November 2010 / Published: 10 November 2010
Cited by 50 | PDF Full-text (815 KB) | HTML Full-text | XML Full-text
Abstract
Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype [...] Read more.
Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessReview Targeted Toxins in Brain Tumor Therapy
Toxins 2010, 2(11), 2645-2662; doi:10.3390/toxins2112645
Received: 4 October 2010 / Revised: 20 October 2010 / Accepted: 27 October 2010 / Published: 1 November 2010
Cited by 18 | PDF Full-text (155 KB) | HTML Full-text | XML Full-text
Abstract
Targeted toxins, also known as immunotoxins or cytotoxins, are recombinant molecules that specifically bind to cell surface receptors that are overexpressed in cancer and the toxin component kills the cell. These recombinant proteins consist of a specific antibody or ligand coupled to [...] Read more.
Targeted toxins, also known as immunotoxins or cytotoxins, are recombinant molecules that specifically bind to cell surface receptors that are overexpressed in cancer and the toxin component kills the cell. These recombinant proteins consist of a specific antibody or ligand coupled to a protein toxin. The targeted toxins bind to a surface antigen or receptor overexpressed in tumors, such as the epidermal growth factor receptor or interleukin-13 receptor. The toxin part of the molecule in all clinically used toxins is modified from bacterial or plant toxins, fused to an antibody or carrier ligand. Targeted toxins are very effective against cancer cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated evidence of a tumor response. Currently, clinical trials with some targeted toxins are complete and the final results are pending. This review summarizes the characteristics of targeted toxins and the key findings of the important clinical studies with targeted toxins in malignant brain tumor patients. Obstacles to successful treatment of malignant brain tumors include poor penetration into tumor masses, the immune response to the toxin component and cancer heterogeneity. Strategies to overcome these limitations are being pursued in the current generation of targeted toxins. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Tetanus Toxin C-Fragment: The Courier and the Cure?
Toxins 2010, 2(11), 2622-2644; doi:10.3390/toxins2112622
Received: 11 October 2010 / Accepted: 28 October 2010 / Published: 29 October 2010
Cited by 14 | PDF Full-text (171 KB) | HTML Full-text | XML Full-text
Abstract
In many neurological disorders strategies for a specific delivery of a biological activity from the periphery to the central nervous system (CNS) remains a considerable challenge for successful therapy. Reporter assays have established that the non-toxic C‑fragment of tetanus toxin (TTC), provided [...] Read more.
In many neurological disorders strategies for a specific delivery of a biological activity from the periphery to the central nervous system (CNS) remains a considerable challenge for successful therapy. Reporter assays have established that the non-toxic C‑fragment of tetanus toxin (TTC), provided either as protein or encoded by non-viral naked DNA plasmid, binds pre-synaptic motor neuron terminals and can facilitate the retrograde axonal transport of desired therapeutic molecules to the CNS. Alleviated symptoms in animal models of neurological diseases upon delivery of therapeutic molecules offer a hopeful prospect for TTC therapy. This review focuses on what has been learned on TTC-mediated neuronal targeting, and discusses the recent discovery that, instead of being merely a carrier molecule, TTC itself may well harbor neuroprotective properties. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Toxin-Based Therapeutic Approaches
Toxins 2010, 2(11), 2519-2583; doi:10.3390/toxins2112519
Received: 14 October 2010 / Revised: 25 October 2010 / Accepted: 26 October 2010 / Published: 28 October 2010
Cited by 38 | PDF Full-text (1530 KB) | HTML Full-text | XML Full-text
Abstract
Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in [...] Read more.
Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Figures

Open AccessReview Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy
Toxins 2010, 2(10), 2467-2477; doi:10.3390/toxins2102467
Received: 19 September 2010 / Revised: 15 October 2010 / Accepted: 19 October 2010 / Published: 25 October 2010
Cited by 3 | PDF Full-text (229 KB) | HTML Full-text | XML Full-text
Abstract
A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many [...] Read more.
A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
Open AccessReview Development of Treatment Concepts for the Use of Botulinum Toxin A in Children with Cerebral Palsy
Toxins 2010, 2(9), 2258-2271; doi:10.3390/toxins2092258
Received: 23 July 2010 / Revised: 24 August 2010 / Accepted: 26 August 2010 / Published: 27 August 2010
Cited by 7 | PDF Full-text (947 KB) | HTML Full-text | XML Full-text
Abstract
The treatment of children with cerebral palsy with Botulinum toxin A injections is well established, safe and effective. However, a standardized injection strategy is still missing and the used dosage has escalated over the years. In the recent past, the recommended dosages [...] Read more.
The treatment of children with cerebral palsy with Botulinum toxin A injections is well established, safe and effective. However, a standardized injection strategy is still missing and the used dosage has escalated over the years. In the recent past, the recommended dosages in Europe were, however, reduced due to a better understanding of the relationship between dosage, severe side effects and the kind of anesthesia used. To combine safety and efficacy, the trend tends to a lower dosage, but combined with a more specific selection of injected muscles. The treatment of these key-muscles takes into account the best support for motor development to attain each individual motor milestone. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)

Journal Contact

MDPI AG
Toxins Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
toxins@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Toxins
Back to Top