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ASHLEY SANCHEZ ANDREA POHL VANESSA MICHEL CHLOROTOXIN

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Toxins What is a toxin? A toxin is a poisonous substance that is a specific product of the metabolic activities of a living organism. It is usually very unstable, notably toxic when introduced into the tissues, and typically capable of inducing antibody formation. What is a neurotoxin? A neurotoxin is a substance that damages, destroys, or impairs the functioning of nerve tissue.

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What is chlorotoxin? "Chlorotoxin (CTX), a 4-kD peptide purified from Leiurus quinquestriatus scorpion, is a highly specific marker for glioma cells in biopsy tissues that can target tumors in animal models. Put more simply: "Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus quinquestriatus) which blocks small- conductance chloride channels."

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Why we chose chlorotoxin? We found the venom, Chlorotoxin, to be very interesting because of its possible impact on cancer treatment, especially brain cancer, which has faced many obstacles in finding safe, effective treatment. The source of the toxin is from the venom of a scorpion, which further emphasizes that toxins can be harmful but also potentially beneficial depending on the dose.

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Where does chlorotoxin come from? Chlorotoxin can be purified from crude leiurus, which belongs to scorpion toxin super family.

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Leiurus quinquestriatus Habitat Deathstalkers are found in arid and hyper-arid regions of North Africa and the Middle East. They generally reside under rocks or in abandoned burrows of other animals. They also create their own burrows about 20 cm below rocks. Geographic range "Deathstalkers, Leiurus quinquestriatus, are native to the Oriental, Palearctic, and Palearctic regions. Behaviors Deathstalkers are nocturnal, which helps manage temperature and water balance, important functions for survival in dry habitats. Many species of scorpions dig burrows in the soil. They have flat bodies, allowing them to hide in small cracks, under rocks and under bark

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Mechanism Deathstalker scorpion venom contains chlorotoxin which can have serious effects on the individual who is stung. The shape of chlorotoxin is very important. It is the perfect shape to fit in Chloride ion channels, and irreversibly block them. By doing this, it prevents the muscle cell from receiving an influx of chloride ions which it usually recieves for normal muscle functioning. This results in muscle contraction, and possibly paralysis.

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What to do if stung It is vital to receive medical attention as soon as possible after a sting. Although painful, few people die but those with allergies or heart issues are at greater risk of death if stung. It is important to apply ice in the area of the sting. Treatment includes the administration of anti- venom, pain medication and some antihistamines. Symptoms will vary among patients. Some experience a wide array of symptoms while others experience mild symptoms.

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Anti-venom Treatment Although the Deathstalker Scorpion is regarded as one of the most toxic scorpions, stings are not usually fatal. There is an anti-venom which is used for the treatment of Deathstalker stings. It has no effect on Chlorotoxin proteins that are already blocking Chloride channels, but rather works by changing the shape of Chlorotoxin so it cannot bind and block Chloride channels. Preventing the problem from getting worse.

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Ancient Uses of Scorpion Venom In imperial China, scorpion venom was used to treat ailments such as mumps and tetanus In India, whole scorpions were dipped in mustard oil and rubbed on arthritic joints to treat pain

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Chlorotoxin and Gliomas In 1996, Ullrich and Sontheimer found that Chlorotoxin was effective in blocking chloride channels in glial cells by as much as 80%. They also found that cell proliferation decreased as chloride channels were blocked, suggesting a link between the chloride channels and growth control. Soroceanu et al (1998) found the toxin probably binds to glioma-specific chloride ion channels or another receptor that affects the channels activity.

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Chlorotoxin and Other Cancer Cells In 2002, Lyons et al found that Chlorotoxin can bind to a number of tumor cells, even though they have different membrane composition. They stained tissues from 48 various peripheral tumors of neuroectodermal origin, 63 from gliomas and 151 comparison tissue samples with a chlorotoxin derivative. Comparison tissue samples were healthy tissues from the same organ. Over 95% of the glioma cells showed specific binding of the chlorotoxin derivative. The chlorotoxin derivative bound well to other brain tumor cells, as well as melanoma, carcinoma and pheochromacytoma tissues. Healthy tissues were mostly untouched by the toxin.

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Medical Possibilities for Chlorotoxin Dr. Steven Rosenfeld is conducting a series of trials at the NewYork-Presbyterian using radioactive and non-radioactive chlorotoxin to inhibit angiogenesis, or the tumors ability to grow blood vessels. The first clinical, which has been completed, saw radioactive chlorotoxin delivered locally to the brain tumor site via a thin catheter. In the second trial, which is currently underway, patients are receiving a non-radioactive chlorotoxin delivered intravenously. The third trial will see patients receiving radioactive chlorotoxin intravenously.

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Medical Possibilities for Chlorotoxin Tumor Paint Dr. Jim Olson is working on developing a chlorotoxin biconjugate that will stain cancer cells so surgeons can more easily remove the tumor during surgery. Tumor Paint attaches to cancerous cells and illuminates them so surgeons can distinguish them from healthy cells.

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CTX Nanoparticles Chlorotoxin (CTX) is an up and coming important toxin in the development of glioma- specific nanoparticles. Chloride channels are CTX receptors, and matrix metalloproteinase-2 (MMP-2) has been identified as a second CTX receptor. MMPs are a family of enzymes that are responsible for specifically cleaving components of the extracellular matrix. MMP-2 is upregulated in gliomas and other related cancers.

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Medical Possibilities for Chlorotoxin Gene Therapy In a study by Kievit et al, researchers developed nanoparticles that had DNA encoding green fluorescent expression and attached them to chlorotoxin. They studied gene delivery to glioma cells in mice. There was enhanced uptake of these particles in cancer cells, as evidenced by higher gene expression. The DNA-attached chlorotoxin saw much higher localized expression of the green fluorescent protein in tumor cells

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Medical Possibilities for Chlorotoxin The research on this toxin has shown the great potential it has to further cancer treatment. Its ability to affect cancer cells without harming healthy cells makes it a safe alternative to current treatments such as chemotherapy. It can potentially help inhibit growth of tumors, deliver genes that can act on cancer cells, and light up tumors, helping surgeons remove whole tumors while leaving healthy tissue unharmed.

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The Good Chlorotoxin was originally isolated from venom of deathstalkers and is now being used in cancer research and treatment. More research is being done in regards to the possible use of other components of deathstalkers venom in the treatment of diabetes because as channels on which the neurotoxins act have been linked to the regulation of insulin. However, such research is still in its early stages. Scorpions are also good bio-indicators, as they are K-selected equilibrium species that comprise a major group of predatory arthropods in arid ecosystems. Their disappearance often indicates habitat degradation and there are programs to conserve terrestrial invertebrates that often target scorpions.

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The Bad Deathstalker scorpions use venom as a defense mechanism. As a result, this can have very painful (and sometimes deadly) consequences for the individual stung.

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Why you should care Chlorotoxin has exhibited itself to be a useful peptide in the research and treatment of different cancers and medical issues. This toxin has a major impact on the medical world, as well as in the lives of those with cancer. The main take-home message that is further exhibited by chlorotoxin is that toxins can be harmful AND helpful.

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Works Cited Fu, y., An, N., Li, K., Zheng, Y., Liang, A. (2011). Chlorotoxin-conjugated nanoparticles as potential glioma-targeted drugs. Journal of Neuro- Oncology. 107:457-462. Kievit, F. M., Veiseh, O., Fang, C., Bhattarai, N., Lee, D., Ellenbogen, R. -G., and Zhang, M. (2010). Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano, 4.8: 4587-94. Lyons, S. A., O'Neal, J. and Sontheimer, H. (2002), Chlorotoxin, a scorpion- derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia, 39: 162173. Soroceanu, L., Gillespie, Y., Khazaeli, M. B., and Sontheimer, H. (1998). Use of chlorotoxin for targeting of primary brain tumors. Cancer Research, 1.58: 4871-9. Ullrich, N. and Sontheimer, H. (1996). Biophysical and pharmacological characterization in human astrocytoma cells. American Journal of Physiology, 270.5: 1511-21.

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Works Cited http://www.merriam-webster.com/dictionary/toxin http://medical-dictionary.thefreedictionary.com/neurotoxin http://www.ncbi.nlm.nih.gov/pubmed/12112367 http://en.wikipedia.org/wiki/Chlorotoxin http://www.alomone.com/p/chlorotoxin/rtc-450/682 http://animaldiversity.org/accounts/Leiurus_quinquestriatus/ http://www.scorpionworlds.com/deathstalker-scorpion/ http://askabiologist.asu.edu/venom/ http://www.wired.com/2014/06/scorpion-venom/ http://nyp.org/deathstalkerscorpion/clinical_trial.html