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Andrea Bolognesi - One of the best experts on this subject based on the ideXlab platform.

  • primary sequence and 3d structure prediction of the Plant Toxin stenodactylin
    Toxins, 2020
    Co-Authors: Rosario Iglesias, Letizia Polito, Massimo Bortolotti, Manuela Pedrazzi, Lucia Citores, J M Ferreras, Andrea Bolognesi
    Abstract:

    Stenodactylin is one of the most potent type 2 ribosome-inactivating proteins (RIPs); its high toxicity has been demonstrated in several models both in vitro and in vivo. Due to its peculiarities, stenodactylin could have several medical and biotechnological applications in neuroscience and cancer treatment. In this work, we report the complete amino acid sequence of stenodactylin and 3D structure prediction. The comparison between the primary sequence of stenodactylin and other RIPs allowed us to identify homologies/differences and the amino acids involved in RIP toxic activity. Stenodactylin RNA was isolated from Plant caudex, reverse transcribed through PCR and the cDNA was amplificated and cloned into a plasmid vector and further analyzed by sequencing. Nucleotide sequence analysis showed that stenodactylin A and B chains contain 251 and 258 amino acids, respectively. The key amino acids of the active site described for ricin and most other RIPs are also conserved in the stenodactylin A chain. Stenodactylin amino acid sequence shows a high identity degree with volkensin (81.7% for A chain, 90.3% for B chain), whilst when compared with other type 2 RIPs the identity degree ranges from 27.7 to 33.0% for the A chain and from 42.1 to 47.7% for the B chain.

  • ricin an ancient story for a timeless Plant Toxin
    Toxins, 2019
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Massimo Bortolotti, Giulia Calafato, Andrea Bolognesi
    Abstract:

    The castor Plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for several biocrimes. This manuscript intends to give the reader an overview of ricin, focusing on the historical path to the current knowledge on this protein. The main steps of ricin research are here reported, with particular regard to its enzymatic activity, structure, and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation between bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been used to develop immunoToxins for the elimination of unwanted cells, mainly cancer cells; some of these immunoconjugates gave promising results in clinical trials but also showed critical limitation.

  • Ricin: An Ancient Story for a Timeless Plant Toxin
    2019
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Massimo Bortolotti, Giulia Calafato, Andrea Bolognesi
    Abstract:

    The castor Plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for biocrimes in several cases. Here, the main steps of ricin research are reported with particular regards to its enzymatic activity, structure and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation amongst bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been of great utility to develop a number of immunoToxins specific for the elimination of unwanted cells, mainly cancer cells; some of these immunoToxins gave promising results also in clinical trials.

  • potential therapeutic application of the Plant Toxin saporin s6
    Clinical and Experimental Pharmacology, 2014
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Andrea Bolognesi
    Abstract:

    In a recent review, we focused on possible applications of the Plant Toxin saporin-S6 in cancer therapy [1]. However, this protein’s therapeutic potential has been demonstrated in many other fields. Saporin-S6 belongs to the Ribosome-Inactivating Protein (RIP) family, a class of enzymes widely distributed amongst Plants that damage ribosomes in an irreversible manner causing protein synthesis arrest and cell death. RIPs are mainly classified as type 1, single chain proteins with enzymatic activity, or type 2, consisting of an active A chain coupled by a disulphide bond to a lectin B chain [2]. RIPs cleave a specific adenine essential for the binding of elongation-factors to the ribosomal large subunit. In vitro, RIPs also deadenilate different substrates, such as mRNA, tRNA, DNA and poly (A); for this reason, RIPs’ enzymatic activity has been afterwards defined as Polynucleotide: Adenosine Glycosylase (PNAG) [3].

Andrew Burgess - One of the best experts on this subject based on the ideXlab platform.

Caroline G. Roberts - One of the best experts on this subject based on the ideXlab platform.

  • Role of endoplasmic reticulum stress induction by the Plant Toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells
    British Journal of Cancer, 2013
    Co-Authors: Rachael A. Mccloy, E. J. Shelley, Caroline G. Roberts, Ebru Boslem, Trevor J. Biden, Robert Ian Nicholson, Julia Margaret Wendy Gee, Elizabeth A. Musgrove, R L Sutherland, Andrew Burgess
    Abstract:

    Background: Persin is a Plant Toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved. Methods: The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference. Results: Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells. Conclusion: The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance.

  • Role of endoplasmic reticulum stress induction by the Plant Toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells.
    British journal of cancer, 2013
    Co-Authors: Rachael A. Mccloy, E. J. Shelley, Caroline G. Roberts, Ebru Boslem, Trevor J. Biden, Robert Ian Nicholson, Julia Margaret Wendy Gee, Rachel Sutherland, Elizabeth A. Musgrove, Andrew Burgess
    Abstract:

    Role of endoplasmic reticulum stress induction by the Plant Toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells

  • Synergistic cytotoxicity between tamoxifen and the Plant Toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism.
    Molecular cancer therapeutics, 2007
    Co-Authors: Caroline G. Roberts, Trevor J. Biden, Ebru Gurisik, Robert L. Sutherland, Alison J. Butt
    Abstract:

    Phytochemicals have provided an abundant source of novel therapeutics for the treatment of human cancers. We have previously described a novel Plant Toxin, persin, derived from avocado leaves, which has unique in vivo actions in the mammary epithelium and Bim-dependent, cytotoxic effects in human breast cancer cells in vitro. Compounds structurally similar to persin, such as the polyunsaturated fatty acid, conjugated linoleic acid, can attenuate steroid hormone receptor signaling and modulate the response of breast cancer cells to antiestrogens. Here, we provide evidence that persin may have similar effects by showing its potent proapoptotic synergy with the antiestrogen 4-hydroxytamoxifen. However, although persin transcriptionally down-regulates estrogen receptor (ER) expression, unlike conjugated linoleic acid, it also shows efficacy in ER-negative breast cancer cells, both alone and in combination with 4-hydroxytamoxifen, whereas normal breast epithelial cells are unaffected, suggesting it may act via a distinct, ER-independent mechanism. These proapoptotic synergistic interactions are associated with increased de novo ceramide synthesis and are dependent on expression of the proapoptotic protein Bim. These data show that persin should be further investigated as a potential novel cancer therapeutic agent because it significantly enhances the sensitivity of breast cancer cells to the cytotoxic effects of tamoxifen, regardless of their ER status, while displaying apparent specificity for the malignant phenotype.

  • A novel Plant Toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells
    Molecular cancer therapeutics, 2006
    Co-Authors: Alison J. Butt, Caroline G. Roberts, Alan A. Seawright, Peter B. Oelrichs, John K. Macleod, Tracy Y.e. Liaw, Maria Kavallaris, Tiffany J. Somers-edgar, Gillian M. Lehrbach, Colin K. W. Watts
    Abstract:

    Phytochemicals have provided an abundant and effective source of therapeutics for the treatment of cancer. Here we describe the characterization of a novel Plant Toxin, persin, with in vivo activity in the mammary gland and a p53-, estrogen receptor-, and Bcl-2-independent mode of action. Persin was previously identified from avocado leaves as the toxic principle responsible for mammary gland-specific necrosis and apoptosis in lactating livestock. Here we used a lactating mouse model to confirm that persin has a similar cytotoxicity for the lactating mammary epithelium. Further in vitro studies in a panel of human breast cancer cell lines show that persin selectively induces a G2-M cell cycle arrest and caspase-dependent apoptosis in sensitive cells. The latter is dependent on expression of the BH3-only protein Bim. Bim is a sensor of cytoskeletal integrity, and there is evidence that persin acts as a microtubule-stabilizing agent. Due to the unique structure of the compound, persin could represent a novel class of microtubule-targeting agent with potential specificity for breast cancers.

Letizia Polito - One of the best experts on this subject based on the ideXlab platform.

  • primary sequence and 3d structure prediction of the Plant Toxin stenodactylin
    Toxins, 2020
    Co-Authors: Rosario Iglesias, Letizia Polito, Massimo Bortolotti, Manuela Pedrazzi, Lucia Citores, J M Ferreras, Andrea Bolognesi
    Abstract:

    Stenodactylin is one of the most potent type 2 ribosome-inactivating proteins (RIPs); its high toxicity has been demonstrated in several models both in vitro and in vivo. Due to its peculiarities, stenodactylin could have several medical and biotechnological applications in neuroscience and cancer treatment. In this work, we report the complete amino acid sequence of stenodactylin and 3D structure prediction. The comparison between the primary sequence of stenodactylin and other RIPs allowed us to identify homologies/differences and the amino acids involved in RIP toxic activity. Stenodactylin RNA was isolated from Plant caudex, reverse transcribed through PCR and the cDNA was amplificated and cloned into a plasmid vector and further analyzed by sequencing. Nucleotide sequence analysis showed that stenodactylin A and B chains contain 251 and 258 amino acids, respectively. The key amino acids of the active site described for ricin and most other RIPs are also conserved in the stenodactylin A chain. Stenodactylin amino acid sequence shows a high identity degree with volkensin (81.7% for A chain, 90.3% for B chain), whilst when compared with other type 2 RIPs the identity degree ranges from 27.7 to 33.0% for the A chain and from 42.1 to 47.7% for the B chain.

  • ricin an ancient story for a timeless Plant Toxin
    Toxins, 2019
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Massimo Bortolotti, Giulia Calafato, Andrea Bolognesi
    Abstract:

    The castor Plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for several biocrimes. This manuscript intends to give the reader an overview of ricin, focusing on the historical path to the current knowledge on this protein. The main steps of ricin research are here reported, with particular regard to its enzymatic activity, structure, and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation between bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been used to develop immunoToxins for the elimination of unwanted cells, mainly cancer cells; some of these immunoconjugates gave promising results in clinical trials but also showed critical limitation.

  • Ricin: An Ancient Story for a Timeless Plant Toxin
    2019
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Massimo Bortolotti, Giulia Calafato, Andrea Bolognesi
    Abstract:

    The castor Plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for biocrimes in several cases. Here, the main steps of ricin research are reported with particular regards to its enzymatic activity, structure and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation amongst bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been of great utility to develop a number of immunoToxins specific for the elimination of unwanted cells, mainly cancer cells; some of these immunoToxins gave promising results also in clinical trials.

  • Plant Toxin based immunoToxins for cancer therapy a short overview
    Biomedicines, 2016
    Co-Authors: Letizia Polito, Alice Djemil, Massimo Bortolotti
    Abstract:

    ImmunoToxins are chimeric proteins obtained by linking a Toxin to either an intact antibody or an antibody fragment. Conjugation can be obtained by chemical or genetic engineering, where the latter yields recombinant conjugates. An essential requirement is that the target molecule recognized by the antibody is confined to the cell population to be deleted, or at least that it is not present on stem cells or other cell types essential for the organism’s survival. Hundreds of different studies have demonstrated the potential for applying immunoToxins to many models in pre-clinical studies and in clinical trials. ImmunoToxins can be theoretically used to eliminate any unwanted cell responsible for a pathological condition. The best results have been obtained in cancer therapy, especially in hematological malignancies. Among Plant Toxins, the most frequently employed to generate immunoToxins are ribosome-inactivating proteins, the most common being ricin. This review summarizes the various approaches and results obtained in the last four decades by researchers in the field of Plant Toxin-based immunoToxins for cancer therapy.

  • potential therapeutic application of the Plant Toxin saporin s6
    Clinical and Experimental Pharmacology, 2014
    Co-Authors: Letizia Polito, Maria Giulia Battelli, Andrea Bolognesi
    Abstract:

    In a recent review, we focused on possible applications of the Plant Toxin saporin-S6 in cancer therapy [1]. However, this protein’s therapeutic potential has been demonstrated in many other fields. Saporin-S6 belongs to the Ribosome-Inactivating Protein (RIP) family, a class of enzymes widely distributed amongst Plants that damage ribosomes in an irreversible manner causing protein synthesis arrest and cell death. RIPs are mainly classified as type 1, single chain proteins with enzymatic activity, or type 2, consisting of an active A chain coupled by a disulphide bond to a lectin B chain [2]. RIPs cleave a specific adenine essential for the binding of elongation-factors to the ribosomal large subunit. In vitro, RIPs also deadenilate different substrates, such as mRNA, tRNA, DNA and poly (A); for this reason, RIPs’ enzymatic activity has been afterwards defined as Polynucleotide: Adenosine Glycosylase (PNAG) [3].

Rachael A. Mccloy - One of the best experts on this subject based on the ideXlab platform.