Colchicine--Update on mechanisms of action and therapeutic uses

Abstract

Objectives: To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions.

Methods: We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed.

Results: The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis.

Conclusion: Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.

Keywords: Colchicines; Inflammation; Mechanism of action; Pharmacokinetics; Therapeutic use.

Figure 1. Summary of the main anti-inflammatory mechanisms of action of colchicines

Dashed lines refer to inhibitory activities and continuous lines to stimulatory activities of colchicine. The main mechanisms of action include the following: A. Colchicine inhibits activation of innate immunity, NALP3 inflammasome activation, CASPASE-1 activation; inhibits release of chemotactic factor release from neutrophils and then neutrophil recruitment; B. At low concentrations, colchicine inhibits expression of E-selectin on endothelial cells and prevents neutrophil adhesion. At high concentrations, colchicine promotes shedding of L-selectin from neutrophils and prevents further recruitment; C. Colchicine inhibits neutrophil activation and release of IL1, IL8, and superoxide; D. Colchicine promotes maturation of dendritic cells to act as antigen presenting cells; E. Colchicine inhibits vascular endothelial growth factor (VEGF) and endothelial proliferation. CASPASE= cysteine-dependent aspartate-directed proteases, CCF= crystal-derived chemotactic factor, MSU=monosodium urate (gout) crystals, MICL= myeloid inhibitory C-type lectin-like receptor, NALP3=NACHT-LRRPYD-containing protein 3, TLR=toll-like receptors, MyD88= myeloid differentiation primary response gene 88, VEGF= vascular endothelial growth factor.

Figure 2. Summary of the effects of colchicine on macrophages

Dashed lines refer to inhibitory activities and continuous lines to stimulatory activities of colchicine. A. Colchicine inhibits activation of P2X2 and P2X7 receptors and blocks cationic dye uptake (via recruitment of the pannexin-1 membrane pore) and further pro-inflammatory cascades without affecting cell death. B. Colchicine inhibits the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, possibly via inhibition of assembly of NALP3 with Apoptosis associated Speck like protein containing Caspase recruitment domain (ACS); C. Colchicine inhibits the RhoA/ Rho effector kinase (ROCK) pathway via cytoskeleton rearrangement and thus the activation of caspase- 1 and downstream maturation and release of IL1β; D. Colchicine inhibits release of various substances including reactive oxygen (ROS), nitrite oxide (NO) and tumor necrosis factor (TNF)α. Caspase-1= cysteine-dependent aspartate-directed proteases-1, IL= interleukin, LPS= lipopolysaccharide, P2X2 and P2X7= purinergic receptors.