Chlorotoxin
Encyclopedia
Chlorotoxin is a 36-amino acid
peptide
found in the venom
of the deathstalker scorpion
(Leiurus quinquestriatus) which blocks small-conductance chloride channel
s. The fact that chlorotoxin binds preferentially to glioma
cells has allowed the development of new methods, that still are under investigation, for the treatment and diagnosis of several types of cancer.
Chlorotoxin has a considerable sequence homology to the class of small insectotoxins.
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.
CLTX has the ability to interact with chloride channels in membrane protein in glioma
cells, so this prevents transmembrane chloride fluxes but this interaction does not happen for the neurons and normal glial cells. This suggests a potential treatment 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.
CTX: Cy5.5 bioconjugate which is a combination of chlorotoxin and a fluorescent material named, Cy5.5
has been recently used by Researchers at Seattle Children’s Hospital Research Institute and Fred Hutchinson Cancer Research Center
to demarcate cancer cells from the surrounding normal cells. This gives surgeons a better chance of removing all of the cancerous cells without injuring the surrounding healthy tissue. CTX: Cy5.5 is a fluorescent molecule emitting photons in the near infrared
spectrum and hence can be visualized in the operating room with the aid of infrared glasses. Studies in mouse models have shown that 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.
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
found in the venom
Venom
Venom is the general term referring to any variety of toxins used by certain types of animals that inject it into their victims by the means of a bite or a sting...
of the deathstalker scorpion
Deathstalker
The deathstalker , is a species of scorpion, a member of the Buthidae family. It is also known as Palestine yellow scorpion, Omdurman scorpion, Israeli desert scorpion and numerous other colloquial names, which generally originate from the commercial captive trade of the animal...
(Leiurus quinquestriatus) which blocks small-conductance chloride channel
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
s. The fact that chlorotoxin binds preferentially to glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
cells has allowed the development of new methods, that still are under investigation, for the treatment and diagnosis of several types of cancer.
Source
Chlorotoxin can be purified from crude leiurus, which belongs to scorpion toxin super family.Chemistry
Chlorotoxin is a small toxin and at pH 7 is highly positive charged. It is a peptide consisting of 30–35 amino acids and 4 disulfide bonds; eight cysteine amino acids among its total number of amino acids present in the structure of this peptide are connected with four disulfide bonds.Chlorotoxin has a considerable sequence homology to the class of small insectotoxins.
Target
Chlorotoxin is the first reported high-affinity peptide ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
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 ±20 seconds after injection which progressed to a rigid paralysis of the walking and pincer legs that was complete within an additional ±40 seconds. 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 0.5µg/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.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.CLTX has the ability to interact with chloride channels in membrane protein in glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
cells, so this prevents transmembrane chloride fluxes but this interaction does not happen for the neurons and normal glial cells. This suggests a potential treatment 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.
CTX: Cy5.5 bioconjugate which is a combination of chlorotoxin and a fluorescent material named, Cy5.5
Cyanine
Cyanine is a non-systematic name of a synthetic dye family belonging to polymethine group. Cyanines have many uses as fluorescent dyes, particularly in biomedical imaging...
has been recently used by Researchers at Seattle Children’s Hospital Research Institute and Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
The Fred Hutchinson Cancer Research Center, is one of the world’s leading cancer research institutes...
to demarcate cancer cells from the surrounding normal cells. This gives surgeons a better chance of removing all of the cancerous cells without injuring the surrounding healthy tissue. CTX: Cy5.5 is a fluorescent molecule emitting photons in the near infrared
Infrared
Infrared light is electromagnetic radiation with a wavelength longer than that of visible light, measured from the nominal edge of visible red light at 0.74 micrometres , and extending conventionally to 300 µm...
spectrum and hence can be visualized in the operating room with the aid of infrared glasses. Studies in mouse models have shown that 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.