Colchicine is a toxic
natural productA natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...
and
secondary metaboliteSecondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of organisms. Unlike primary metabolites, absence of secondary metabolities does not result in immediate death, but rather in long-term impairment of the organism's...
, originally extracted from plants of the genus
ColchicumColchicum is a genus of flowering plants containing around sixty species of perennial plants which grow from corms. It is a member of family Colchicaceae, and is native to West Asia and part of the Mediterranean coast....
(
Autumn crocusAutumn Crocus could refer to one of two species of flowering plant:* the Autumn Crocus Crocus nudiflorus* the Meadow Saffron Colchicum autumnale, which is also known as Autumn Crocus...
,
Colchicum autumnale, also known as "Meadow saffron"). It was used originally to treat rheumatic complaints, especially
goutGout is a disease hallmarked by elevated levels of uric acid in the bloodstream. In this condition, crystals of monosodium urate or uric acid are deposited on the articular cartilage of joints, tendons, and surrounding tissues...
, and still finds use for these purposes today. It was also prescribed for its
catharticIn medicine, a cathartic is a substance which accelerates defecation.This is in contrast to a laxative, which is a substance which eases defecation, usually by softening the stool. It is possible for a substance to be both a laxative and a cathartic...
and emetic effects. Colchicine's present medicinal use is in the treatment of gout and
familial Mediterranean feverFamilial Mediterranean Fever , also known as the Armenian disease is a hereditary inflammatory disorder that affects groups of people originating from around the Mediterranean Sea...
; it can also be used as initial treatment for
pericarditisPericarditis is an inflammation of the pericardium .-Classification:Pericarditis can be classified according to the composition of the inflammatory exudate.Types include:* serous* purulent* fibrinous...
and preventing recurrences of the condition. It is also being investigated for its use as an anti-
cancerCancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
drug. In neurons,
axoplasmic transportAxoplasmic transport, also called axonal transport, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other cell parts to and from a neuron's cell body, through the cytoplasm of its axon...
is disrupted by colchicine.
History
Colchicum extract was first described as a treatment for gout in
De Materia Medica by Pedanius Dioscorides in the first century
CECommon Era, abbreviated as CE, is a designation for the calendar system most commonly used world-wide for numbering the year part of the date...
. Colchicine, an
alkaloidAlkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of...
, was first isolated in 1820 by the two French chemists P.S. Pelletier and J. Caventon. The alkaloid was later identified as a tricyclic alkaloid, and its pain-relieving and
anti-inflammatoryAnti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids which affect the brain.-Medications:...
effects for gout were linked to its ability to bind with
tubulinTubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
.
Biological function
Colchicine inhibits microtubule polymerization by binding to
tubulinTubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
, one of the main constituents of
microtubuleMicrotubules are one of the components of the cytoskeleton. They have a diameter of 25 nm and length varying from 200 nanometers to 25 micrometers. Microtubules serve as structural components within cells and are involved in many cellular processes including mitosis, cytokinesis, and vesicular...
s. Availability of tubulin is essential to
mitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two daughter nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two daughter cells containing...
, and therefore colchicine effectively functions as a "mitotic poison" or
spindle poisonThese poisons disrupt cellular reproduction by affecting the protein threads which connect the centromere regions of chromosomes, known as spindles.Some spindle poisons:* Mebendazole* Colchicine* Griseofulvin* Vinca Alkaloids* Paclitaxel...
. Since one of the defining characteristics of cancer cells is a significantly increased rate of mitosis, this means that cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. However, the therapeutic value of colchicine against cancer is (as is typical with
chemotherapyChemotherapy, in its most general sense, is the treatment of disease by chemicals especially by killing micro-organisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a cytotoxic standardized treatment regimen...
agents) limited by its toxicity against normal cells.
Apart from inhibiting mitosis, a process heavily dependent on cytoskeletal changes, colchicine also inhibits
neutrophilThis article is about neutrophils, cells of the immune system. For organisms that grow in neutral pH environments see: Neutrophile.Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells in mammals and form an essential part of the innate...
motility and activity, leading to a net
anti-inflammatoryInflammation is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a...
effect. Colchicine also inhibits
uric acidUric acid is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C
5H
4N
4O
3.-Biology:...
(urate) crystal deposition, which is enhanced by a low pH in the tissues, probably by inhibiting oxidation of
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
and subsequent
lactic acidLactic acid , also known as milk acid, is a chemical compound that plays a role in several biochemical processes. It was first isolated in 1780 by a Swedish chemist, Carl Wilhelm Scheele, and is a carboxylic acid with a chemical formula of C
3H
6O
3...
production in leukocytes. The inhibition of uric acid crystals is a vital aspect on the mechanism of gout treatment.
Colchicine as medicine
In August 2009, colchicine won Food and Drug Administration (FDA) approval in the United States as a stand-alone drug for the treatment of acute flares of gout and
familial Mediterranean feverFamilial Mediterranean Fever , also known as the Armenian disease is a hereditary inflammatory disorder that affects groups of people originating from around the Mediterranean Sea...
. It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses an hour apart were effective at combating the condition.
It is also used as an anti-inflammatory agent for long-term treatment of
Behçet's diseaseBehçet disease is a form of vasculitis that can lead to ulceration and other lesions. It can be interpreted as a chronic disturbance in the body’s immune system...
.
The Australian biotechnology company
GiacondaGiaconda is an Australian biotechnology company headquartered in Sydney. The company was founded in 2004 to commercialise a number of drug combinations developed by Professor Thomas Borody, a Sydney-based gastroenterologist.-History:...
has developed a combination therapy to treat constipation-predominant
irritable bowel syndromeIrritable bowel syndrome is a functional gastrointestinal disorder. Also called spastic colon, it is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms...
which combines colchicine with the anti-inflammatory drug
olsalazineOlsalazine is an anti-inflammatory drug used in the treatment of Inflammatory Bowel Disease such as Ulcerative Colitis. It is sold under the name Dipentum.The chemical name is 3,3' -azobis salicylic acid...
.
The British drug development company Angiogene is developing a
prodrugA prodrug is a pharmacological substance that is administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion optimization...
of colchicine,
ZD6126ZD6126 is a vascular-targeting agent and a prodrug of N-acetylcolchinol, related to colchicine. It has shown promising results on cancer tumors in mice....
(also known as ANG453) as a treatment for
cancerCancer is a class of diseases in which a group of cells display uncontrolled growth , invasion , and sometimes metastasis...
.
Colchicine has a relatively low
therapeutic indexThe therapeutic index , is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death. Quantitatively, it is the ratio given by the lethal dose divided by the therapeutic dose...
.
Long term (prophylactic) regimens of oral colchicine are absolutely contraindicated in patients with advanced renal failure (including those on dialysis). 10-20% of a colchicine dose is excreted unchanged by the kidneys. Colchicine is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting. A severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol lowering drugs (statins, fibrates). This neuromuscular condition can be irreversible (even after drug discontinuation). Accompanying dementia has been noted in advanced cases. It may culminate in hypercapnic respiratory failure and death. (Minniti-2005)
Colchicine is "used widely" off-label by naturopaths for a number of treatments, including the treatment of back pain.
Side effects
Side effects include gastro-intestinal upset and
neutropeniaNeutropenia , from Latin prefix neutro- and Greek suffix -πενία is a hematological disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell, in the blood...
. High doses can also damage
bone marrowBone marrow is the flexible tissue found in the hollow interior of bones. In adults, marrow in large bones produces new blood cells. It constitutes 4% of total body weight, i.e...
and lead to
anemiaAnemia is a decrease in normal number of red blood cells or less than the normal quantity of hemoglobin in the blood...
. Note that all of these side effects can result from hyper-inhibition of mitosis.
Toxicity
Colchicine poisoning has been compared to
arsenicArsenic is the chemical element that has the symbol As, atomic number 33 and atomic mass 74.92. Arsenic was first documented by Albertus Magnus in 1250. Arsenic is a notoriously poisonous metalloid with many allotropic forms, including a yellow and several black and grey forms...
poisoning: symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat,
feverFever is a frequent medical sign that describes an increase in internal body temperature to levels above normal...
,
vomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Undesired vomiting may result from many causes, ranging from gastritis or poisoning to brain tumors, or elevated intracranial pressure...
,
diarrheaIn medicine, diarrhea , also spelled diarrhoea , is the condition of having frequent loose or liquid bowel movements. Acute diarrhea is a common cause of death in developing countries and the second most common cause of infant deaths worldwide...
,
abdominal painAbdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
and
kidney failureRenal failure or kidney failure is a situation in which the kidneys fail to function adequately. It is divided into acute and chronic forms; either form may be due to a large number of other medical problems....
. These symptoms may set in as many as 24 hours after the exposure. Onset of multiple-system organ failure may occur within 24 to 72 hours. This includes hypovolemic shock due to extreme vascular damage and fluid loss through the GI tract, which may result in death. Additionally, sufferers may experience kidney damage resulting in low urine output and bloody urine; low white blood cell counts (persisting for several days);
anemiaAnemia is a decrease in normal number of red blood cells or less than the normal quantity of hemoglobin in the blood...
; muscular weakness; and
respiratory failureThe term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
. Recovery may begin within 6 to 8 days. There is no specific antidote for colchicine, although various treatments do exist.
Botanical use
Since
chromosome segregationChromosome segregation is a step in cell reproduction or division, where chromosomes pair off with their similar homologous chromosome. In mitosis, a complete copy of each one is made. In meiosis, one chromosome from each pair migrates to opposite ends of the cell and the genes are split to make a...
is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting
chromosomeA chromosome is an organized structure of DNA and protein that is found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions...
segregation during
meiosisIn biology, meiosis is a process of reductional division in which the number of chromosomes per cell is cut in half. In animals, meiosis always results in the formation of gametes, while in other organisms it can give rise to spores. As with mitosis, before meiosis begins, the DNA in the original...
; half the resulting
gameteA gamete is a cell that fuses with another gamete during fertilization in organisms that reproduce sexually...
s therefore contain no chromosomes, while the other half contain double the usual number of chromosomes (
i.e., diploid instead of haploid as gametes usually are), and lead to embryos with double the usual number of chromosomes (
i.e. tetraploid instead of diploid). While this would be fatal in animal cells, in plant cells it is not only usually well tolerated, but in fact frequently results in plants which are larger, hardier, faster growing, and in general more desirable than the normally diploid parents; for this reason, this type of genetic manipulation is frequently used in breeding plants commercially. In addition, when such a tetraploid plant is crossed with a diploid plant, the triploid offspring will be sterile, which may be commercially useful in itself by requiring growers to buy seed from the supplier, but also can often be induced to create a "seedless" fruit if pollinated (usually the triploid will also not produce pollen, therefore a diploid parent is needed to provide the pollen). This is the method used to create seedless
watermelonWatermelon refers to both fruit and plant of a vine-like herb originally from southern Africa and one of the most common types of melon...
s, for instance. On the other hand, colchicine's ability to induce polyploidy can be exploited to render infertile hybrids fertile, as is done when breeding
triticaleTriticale is a hybrid of wheat and rye first bred in laboratories during the late 19th century. The grain was originally bred in Scotland and Sweden. Commercially available triticale is almost always a 2nd generation hybrid, i.e. a cross between two kinds of triticale...
from
wheatWheat is a worldwide cultivated grass from the Fertile Crescent region of the Near East. In 2007 world production of wheat was 607 million tons, making it the third most-produced cereal after maize and rice...
and
ryeRye is a grass grown extensively as a grain and as a forage crop. It is a member of the wheat tribe and is closely related to barley and wheat. Rye grain is used for flour, rye bread, rye beer, some whiskies, some vodkas, and animal fodder...
. Wheat is typically tetraploid and rye diploid, with the triploid hybrid infertile. Treatment with colchicine of triploid triticale gives fertile hexaploid triticale.
When used to induce
polyploidyPolyploidy occurs in cells and organisms when there are more than two paired sets of chromosomes.Most organisms are normally diploid, meaning they have two sets of chromosomes — one set inherited from each parent. Polyploidy may occur due to abnormal cell division. It is most commonly found in...
in plants, colchicine is usually applied to the plant as a cream. It has to be applied to a growth point of the plant, such as an apical tip, shoot or sucker. Seeds can be presoaked in a colchicine solution before planting. As colchicine is so dangerous, it is worth noting that doubling of chromosome numbers can occur spontaneously in nature, and not infrequently. The best place to look is in regenerating tissue. One way to induce it is to chop off the tops of plants and carefully examine the lateral shoots and suckers to see if any look different. If there is no visual difference
flow cytometryFlow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
can be used for analysis.
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