Chlorotoxin is a 36-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

found in the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of the

deathstalker scorpion The deathstalker (''Leiurus quinquestriatus'') is a species of scorpion, a member of the family Buthidae. It is also known as the Palestine yellow scorpion, Omdurman scorpion, Naqab desert scorpion and by many other colloquial names, which gene ...

(''Leiurus quinquestriatus'') which blocks small-conductance

chloride channel Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Severa ...

s. The fact that chlorotoxin binds preferentially to

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

cells has allowed the development of methods for the treatment and diagnosis of several types of cancer.

Sources

Chlorotoxin can be purified from crude leiurus, which belongs to the

scorpion toxin Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, volt ...

protein

superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...

Chemistry

Chlorotoxin is a small toxin and at pH 7 is highly positively charged. It is a

consisting of 36

s, with 8

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

s forming 4

disulfide bond In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

s. Chlorotoxin has a considerable

sequence homology Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spe ...

to the class of small insectotoxins.

Target

Chlorotoxin is the first reported high-affinity peptide

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

for Cl⁻ channels and it blocks small conductance chloride channels. Each chloride channel can be closed by only one ligand molecule. Using a recombinant chlorotoxin it was demonstrated that chlorotoxin specifically and selectively interacts with MMP-2 isoforms which are specifically upregulated in gliomas and related cancers, but are not normally expressed in brain.

Toxicity

Chlorotoxin immobilizes the envenomated prey. Duration of paralysis depends on the amount of chlorotoxin injected. In crayfish, chlorotoxin at 1.23-2.23 µg/g body wt produced a loss of motor control beginning about 20 seconds after injection which progressed to a rigid paralysis of the walking and pincer legs that was complete about forty seconds later. Within ±90 s of injection the tail musculature was immobilized. No recovery was noted for 6 hours, at which time the crayfish were destroyed. At 0.5 µg/g, chlorotoxin induced the same progressive paralysis with a slower onset. Recovery of crayfish was noted after 2 hours. The injection on insects produced similar results to those observed in crayfish.

Possible therapeutic use

The fact that chlorotoxin binds preferentially to glioma cells compared with non-neoplastic cells or normal brain has allowed the development of new methods for the treatment and diagnosis of several types of cancer. Chlorotoxin has the ability to interact with chloride channels in membrane protein in

cells, so this prevents

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

chloride fluxes but this interaction does not happen for the neurons and normal glial cells. This suggests a potential treatment for cancer. A report showed the anti-invasive effect of chlorotoxin on glioma cells mediated by its interaction with MMP-2, which allows the penetration of normal and tumor cells through tissue barriers. Chlorotoxin exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. This result implies the use of chlorotoxin as a highly effective drug of therapeutic potential for diseases that involve the activity of MMP-2. TM-601 which is the synthetic version of chlorotoxin is under phase II clinical trial. Iodine-131-TM-601 is used to treat malignant glioma. TM-601 is also a candidate for targeting gliomas because it crosses blood-brain and tissue barriers and binds to malignant brain tumor cells without affecting healthy tissue. Phase II trials are being conducted on the use of chlorotoxin for imaging and radio therapy in glioma. Chlorotoxin:Cy5.5 (CTX:Cy5.5), which is a bioconjugate of chlorotoxin and a

fluorescent Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...

dye named Cy5.5, was used by researchers at Seattle Children's Hospital Research Institute and

Fred Hutchinson Cancer Research Center The Fred Hutchinson Cancer Center, formerly known as the Fred Hutchinson Cancer Research Center and also known as Fred Hutch or The Hutch, is a cancer research institute established in 1975 in Seattle, Washington. History The center grew out o ...

to distinguish cancer cells from the surrounding normal cells. This could enable surgeons to remove cancerous cells without injuring the surrounding healthy tissue. CTX:Cy5.5 is a fluorescent molecule emitting photons in the near

infrared Infrared (IR), sometimes called infrared light, is electromagnetic radiation (EMR) with wavelengths longer than those of visible light. It is therefore invisible to the human eye. IR is generally understood to encompass wavelengths from around ...

spectrum and hence can be visualized in the operating room with the aid of infrared glasses. Studies in mouse models have shown that CTX:Cy5.5 can identify tumors with as few as 2000 cancer cells, making it 500 times more sensitive than MRI. Treated animals exhibited no neurologic or behavioral deficits, and postmortem studies revealed no evidence of neuropathy. In 2015, clinical trials were beginning for this "Tumor Paint."

In popular culture

In the episode "

Both Sides Now "Both Sides, Now" is a song by Canadian singer-songwriter Joni Mitchell. First recorded by Judy Collins, it appeared on the US singles chart during the fall of 1968. The next year it was included on Mitchell's album '' Clouds'', and became one ...

" of medical drama '' House MD'',

House A house is a single-unit residential building. It may range in complexity from a rudimentary hut to a complex structure of wood, masonry, concrete or other material, outfitted with plumbing, electrical, and heating, ventilation, and air condi ...

suggests using a scorpion derived toxin to paint the pancreas and view it under infrared light to look for tumors too small to detect by

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

References

{{Reflist Scorpion toxins Experimental cancer drugs Ion channel toxins Chloride channel blockers