Begell House Inc.
Onco Therapeutics
OT
2694-4642
4
3-4
2013
Structure and Biological Activity of Botulinum Neurotoxins and Application to Cancer Therapy
197-212
10.1615/ForumImmunDisTher.2014011238
Kei Roger
Aoki
Neurotoxin Research Program, Discovery Research Biological Sciences, Allergan, Inc., Irvine, California
Ester
Fernandez-Salas
Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, Michigan
botulinum neurotoxin
SNARE proteins
retargeted endopeptidases
cancer
protein stapling
biotherapeutics
targeted exocytosis modulators
targeted secretion inhibitors
Botulinum neurotoxin (BoNT) has historically been studied as the botulism-causing protein produced by the anaerobic bacillus, Clostridium botulinum. However, research interest in BoNT has recently shifted toward the mechanisms by which it can be utilized to decipher basic neuronal biology, treat neuromuscular disorders and pain, and be used as an anticancer treatment. BoNT has been shown to inhibit the release of neurotransmitters and factors required for tumor growth and maintenance, altering the tumor microenvironment. Treatment with BoNT can also enhance the delivery of chemotherapeutic agents, serve as an adjuvant to cancer chemotherapy, mitigate cancer-related side effects (i.e., pain and excess saliva), and potentiate the effects of radiotherapy. Most recently, work with BoNT has focused on the direct effects of the toxin in tumor cells. Through protein retargeting and recombinant technology, the activity of BoNT can be specifically delivered to cancer cells. This review summarizes the variety of ways in which BoNT has been used as an adjuvant for cancer therapy, discusses the potential mechanisms that describe how BoNT may affect growth and apoptosis of tumor cells, and highlights the promise these new biomolecules have as a safer and more effective anticancer therapeutic.
Use of Botulinum Neurotoxin in Cranial Nerve Paralysis due to Nasopharyngeal Carcinoma
213-218
10.1615/ForumImmunDisTher.2014008421
Ozge
Ilhan-Sarac
Department of Ophthalmology, Ankara Ataturk Research and Training Hospital, Ankara, Turkey
Hande Taylan
Sekeroglu
Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
Ali Sefik
Sanac
Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
Enis
Ozyar
Department of Radiation Oncology, Acibadem University School of Medicine, Istanbul, Turkey
Cumhur
Sener
Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey
nasopharyngeal carcinoma
cranial nerve palsy
botulinum neurotoxin
Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx arising from the epithelial cells. Extension of the primary tumor to the adjacent tissues can cause cranial nerve (CN) palsies. Although all CNs can be involved, the CN VI, CN V, CN VIII, CN IX, and CN XII are the most commonly affected. Isolated involvement frequently occurs in the CN V or CN VI. Nearly 70% of patients with CN palsy associated with NPC show improvement after radiotherapy. The recovery duration is generally within 6 months; therefore, botulinum neurotoxin injection should be considered for these patients to alleviate the complaints within this time period.
Bacterial Toxins in Cancer Immunotherapy
219-239
10.1615/ForumImmunDisTher.2014008368
Irena
Adkins
Sotio a.s., Prague, Czech Republic; and Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
Lenka
Sadilkova
Sotio a.s., Prague, Czech Republic; and Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
Lenka
Palova-Jelinkova
Sotio a.s., Prague, Czech Republic; and Department of Immunology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
bacterial toxin
cancer immunotherapy
toxoid
antigen delivery
toxin-targeted therapy
immunotoxin
adjuvants
Bacterial protein toxins perfected through evolution in pathogenic bacteria play an important role in infectious diseases and share the ability to target various intracellular proteins to modulate host immune responses. Several bacterial toxins and their nontoxic mutants have been intensively studied over the past decades to harness their abilities to enter host cells and deliver drugs for a direct elimination of cancer cells, to carry antigenic epitopes to stimulate adaptive T cell responses, and to boost immunity as adjuvants. Some of these toxins may be utilized in the diagnostics of cancer. Whereas the immunotherapeutic potential of some bacterial toxins is currently being evaluated in various phases of clinical cancer trials, the medical use of others needs to be further established. The major achievement in toxin-targeted immunotherapy is a derivative of lipopolysaccharide monophosphoryl lipid A, muramyl dipeptide derivative Mifamurtide, and Corynebacterium diphtheriae diphtheria toxin-based immunotoxin denileukin diftitox. However, some limitations of the use of bacterial toxins in human immunotherapy remain to be overcome.
Algal-Produced Immunotoxins
241-254
10.1615/ForumImmunDisTher.2014008241
Miller
Tran
Verdant Therapeutics, San Francisco, California
James S.
Hyun
Division of Molecular Biology, The California Center for Algae Biotechnology, University of California, San Diego, California
Michael P.
Mayfield
Verdant Therapeutics, San Francisco, California
Jonathan L.
Torres
Division of Molecular Biology, The California Center for Algae Biotechnology, University of California, San Diego, California
Amy T.
Hoang
Division of Molecular Biology, The California Center for Algae Biotechnology, University of California, San Diego, California
Stephen P.
Mayfield
Division of Molecular Biology, The California Center for Algae Biotechnology, University of California, San Diego, California
algae
immunotoxins
chloroplast
antibodies
Antibody drug conjugates (ADCs) and immunotoxins are second-generation anticancer therapeutics that directly target cancerous cells and deliver toxic molecules that inhibit the cancer's proliferation. They are composed of an antibody domain that binds the target cell, linked to a toxic molecule that inhibits cell proliferation. Utilization of these potent and effective therapies is limited by the high cost and complexity of manufacturing these chimeric molecules. ADCs are currently made by chemically linking an antibody produced by a mammalian cell culture to a toxic drug molecule. Unlike ADCs, immunotoxins utilize protein toxins derived from bacteria or plants, and are often genetically linked to the antibody domain. Protein toxins typically target eukaryotic translations. Because these toxins target eukaryotic translation, they cannot be produced in eukaryotic expression. Production of these chimeric molecules in bacteria is also limited due to the lack of sophisticated protein-folding machinery, which is required to fold complex immunotoxin proteins. To overcome the challenges associated with the production of immunotoxins, chloroplasts of the eukaryotic green alga Chlamydomonas reinhardtii were recently developed as an expression host. Chloroplasts contain complex protein-folding machinery, including chaperones and protein disulfide isomerases, but have a translational apparatus (70S ribosomes and elongation factors) that resembles that of a bacterium, leaving them unharmed by toxins that target the eukaryotic translational apparatus. In addition, chloroplasts are capable of producing multivalent immunotoxins, which increases the capability of these molecules to inhibit the proliferation of cancer cells. Development of this new technology will allow the production of more complex and effective immunotoxins, while potentially reducing the complexity of production of these valuable cancer therapies.
Venoms Can Be a Boon for Cancer Patients
255-273
10.1615/ForumImmunDisTher.2014008152
Sudhir
Kumar
IGNOU-I2IT Centre of Excellence for Advanced Education and Research, Pune, Maharashtra, India
Puja
Sarkar
IGNOU-I2IT Centre of Excellence for Advanced Education and Research, Pune, Maharashtra, India
Ruchi
Jain
Organic Chemistry Division, CSIR National Chemical Laboratory, Pune, Maharashtra, India
venoms
chemotherapy
toxins
anticancer drugs
Cancer is one of the leading causes of death worldwide. Remarkable progress has recently been made toward understanding the proposed hallmarks of cancer development and treatment. Treatment modalities comprise radiation therapy, surgery, chemotherapy, immunotherapy, and hormonal therapy. The use of chemotherapeutics currently remains the predominant option for cancer therapy. One of the major problems with successful cancer therapy using chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. This issue has led to the increased use of anticancer drugs developed from natural resources. The biodiversity of venoms and toxins make them a unique source from which new therapeutics may be developed. Some molecules of venom are under clinical trials and may be utilized in anticancer drug development in the near future. This review discusses the anticancer potential of different venoms, surveys the pharmacology of venom peptides, and assesses their therapeutic prospects.
Possible Molecular Targets of Bee Venom in the Treatment of Cancer: Application and Perspectives
275-315
10.1615/ForumImmunDisTher.2014008125
Nada
Orsolic
Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10000, Croatia
bee venom
melittin
phospholipase A2
apamin
cancer cell
targeted drug delivery
peptide-drug conjugates
The poor efficacy of anticancer drugs is often related to their toxicity as well as to their poor selectivity toward cancer tissue. Use of innovative drug delivery systems can optimize their therapeutic features, protecting the drug against metabolic inactivation, increasing its plasma half-life, and improving both the therapeutic index and the anticancer efficacy of the drug. Many natural products and their active components have recently regained attention as a source of new drug discovery. Honey bee (Apis mellifera) venom, also known as apitoxin, is a very complex mixture of active peptides, enzymes, and amines. Bee venom has been widely used in the treatment of some immune-related diseases, as well as in treatment of cancers in recent times. Components of bee venom, especially melittin, through hyperactivation of phospholipase A2, an influx of Ca2+, and inhibition of nuclear factor-κB and calmodulin could be crucial in the regulation of cancer cell proliferation, apoptosis/necrosis, the process of metastasis, and angiogenesis. In addition, stingins (apamin-derived peptide) represent a novel class of p53 activators and are superior in many aspects to the existing mini-protein antagonists of MDM2/MDMX. This article describes current understanding of the possible molecular targets of bee venom and melittin as a suitable model peptide for drug delivery into cells.