Colchicine—Update on mechanisms of action and therapeutic uses
Introduction
Colchicine is an alkaloid extracted from plants of the genus Colchicum (autumn crocus). The therapeutic use of colchicine has been well documented in gout and familial Mediterranean fever (FMF); it has also been used in other diseases including Behcetʼs disease (BD), pericarditis, coronary artery disease, and other inflammatory and fibrotic conditions. The pharmacotherapeutic mechanism of action of colchicine in diverse disorders is not fully understood. The aim of this article is to review the literature and provide an update on the mechanisms of action and therapeutic uses of colchicine in various inflammatory conditions.
Section snippets
Methods
We performed a PubMed database search for relevant studies published using the search terms “mechanism of action” OR “inflammation” OR “pharmacokinetics” OR “toxicity” OR “therapeutic use” AND “colchicine” between January 1, 2008 to June 15, 2014 and restricted to the English language. The start date was chosen to cover literature published since the topic was last comprehensively reviewed in 2008 [1], [2]. We focused on original articles that provided new information on the mechanisms of
Tubulin disruption and anti-mitotic effect of colchicine
The most studied therapeutic mechanism of action of colchicine is its capacity to bind to tubulins, thereby blocking the assembly and polymerization of microtubules. Microtubules, key components of the cytoskeleton, are made up of αβ-tubulin heterodimers. Microtubules are involved in various cellular processes including maintenance of cell shape, intracellular trafficking, cytokine and chemokine secretion, cell migration, and regulation of ion channels and cell division. Colchicine is a
Conclusion
Colchicine has been the first-line therapy for the treatment of acute gouty arthritis and FMF. Due to the anti-inflammatory and anti-fibrotic activities, the therapeutic use of colchicine has extended beyond arthritis. The exact mechanisms of action underlying its efficacy are not completely understood and remain under active investigation. Current results suggest that colchicine downregulates multiple inflammatory pathways and modulates innate immunity. As demonstrated by this review, there
References (106)
Colchicine update: 2008
Semin Arthritis Rheum
(2009)- et al.
Ribotoxic stress through p38 mitogen-activated protein kinase activates in vitro the human pyrin inflammasome
J Biol Chem
(2013) - et al.
The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-κB through its N-terminal fragment
Blood
(2008) - et al.
The inflammasomes
Cell
(2010) - et al.
Discovery of novel immunostimulants by dendritic-cell-based functional screening
Blood
(2005) - et al.
Colchicine promotes antigen cross-presentation by murine dendritic cells
J Invest Dermatol
(2007) - et al.
Functional microtubules are required for antigen processing by macrophages and dendritic cells
Immunol Lett
(2004) - et al.
Colchicine decreases apoptotic cell death in chronic cyclosporine nephrotoxicity
J Lab Clin Med
(2002) - et al.
Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2
J Biol Chem
(2013) - et al.
Mean platelet volume and β-thromboglobulin levels in familial Mediterranean fever: effect of colchicine use?
Eur J Intern Med
(2012)
Colchicine inhibits intimal hyperplasia and leukocyte VEGF expression in dogs
J Surg Res
Benefit of combined therapy with nicorandil and colchicine in preventing monocrotaline-induced rat pulmonary arterial hypertension
Eur J Pharm Sci
Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia
Lipids Health Dis
MDR1 gene polymorphisms may be associated with Behçetʼs disease and its colchicum treatment response
Gene
Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials
Clin Ther
A randomized controlled trial to evaluate the slow-acting symptom modifying effects of a regimen containing colchicine in a subset of patients with osteoarthritis of the knee
Osteoarthritis Cartilage
Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicenter, double-blind, placebo-controlled, randomized trial
Lancet
Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome
Am J Cardio
International collaborative systematic review of controlled clinical trials on pharmacological treatments for acute pericarditis and its recurrences
Am Heart J
Impact of Colchicine on pericardial inflammatory syndromes—an analysis of randomized controlled trials
Int J Cardiol
Low-dose colchicine for secondary prevention of cardiovascular disease
J Am Coll Cardiol
Colchicine treatment for the prevention of bare metal stent restenosis in diabetic patients
J Am Coll Cardiol
Anti-Inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study
JACC Heart Fail
Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival
Gastroenterology
Colchicine: its mechanism of action and efficacy in crystal-induced inflammation
Curr Rheumatol Rep
Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin
Med Res Rev
The tubulin colchicine domain: a molecular modeling perspective
ChemMedChem
Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment
Cancer Res
Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner
PloS One
Microtubule dynamics control tail retraction in migrating vascular endothelial cells
Mol Cancer Ther
Free tubulin modulates mitochondrial membrane potential in cancer cells
Cancer Res
Polymorphonuclear leukocyte motility in vitro: IV. Colchicine inhibition of chemotactic activity formation after phagocytosis of urate crystals
Arthritis Rheum
Urate crystals, inflammation, and colchicine
Arthritis Rheum
Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis
Arthritis Rheum
Modulation of monosodium urate crystal-induced responses in neutrophils by the myeloid inhibitory C-type lectin-like receptor: potential therapeutic implications
Arthritis Res Ther
Colchicine and methotrexate reduce leukocyte adherence and emigration in rat mesenteric venules
Inflammation
Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils
J Clin Invest
Crystal-induced neutrophil activation. IV. Specific inhibition of tyrosine phosphorylation by colchicine
J Clin Invest
Crystal-induced neutrophil activation: X. Proinflammatory role of the tyrosine kinase Tec
Arthritis Rheum
Technical advance: inhibition of neutrophil chemotaxis by colchicine is modulated through viscoelastic properties of subcellular compartments
J Leukoc Biol
Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low-dose colchicine
Br J Pharmacol
Colchicine modulates oxidative stress in serum and neutrophil of patients with Behçet disease through regulation of Ca²+ release and antioxidant system
J Membr Biol
Gout-associated uric acid crystals activate the NALP3 inflammasome
Nature
Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome
Nat Immunol
The effect of colchicine on pyrin and pyrin interacting proteins
J Cell Biochem
Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis
J Clin Rheumatol
Prolonged reduction in polymorphonuclear adhesion following oral colchicine
Ann Rheum Dis
Treatment with colchicine decreases white cell counts in synovial fluid of asymptomatic knees that contain monosodium urate crystals
J Rheumatol
Albendazole and colchicine modulate LPS-induced secretion of inflammatory mediators by liver macrophages
Bull Exp Biol Med
Lysophospholipids and ATP mutually suppress maturation and release of IL-1 beta in mouse microglial cells using a Rho-dependent pathway
J Immunol
Cited by (580)
A systematic review on the use of Colchicine in Hemorrhagic Stroke
2024, World Neurosurgery: XMolecular Dynamics and Machine Learning reveal distinguishing mechanisms of Competitive Ligands to perturb α,β-Tubulin
2024, Computational Biology and ChemistryA mathematical model of Familial Mediterranean Fever predicts mechanisms controlling inflammation
2023, Clinical Immunology
Author contributions: All authors contributed equally and approved the final version of the manuscript.
Funding source: This review is funded in part by the Singapore National Medical Research Council, transitional award no. (NMRC-TA-0007-2012), the National Institutes of Health, USA (NIH, P30-AG-028716) and a grant from the Duke-NUS Governing Board (Duke/Duke-NUS/RECA/2012/0005) for funding support to V.B.K. and Y.-Y.L.