Colchicine, isolated from Colchicum autumnale, is a drug for acute gouty arthritis known from thousands of years whose use has survived to modernity. Over the past decades, the use for this very old drug extended beyond gout therapy. This was due to the advance in knowledge of (i) association of hyperuricemia and gout with cardiovascular disease, (ii) cytoskeletal microtubules (МТ), and (iii) anti-inflammatory and antifibrotic effects of colchicine, a classical MT-disassembling agent (antitubulin). Here, we present the Bulgarian contribution to colchicine potential in the therapy of cardiovascular disease that has emerged in the early 1970`s in the Laboratory of Electron Microscopy, Medical Institute, Varna, Bulgaria, studying the secretory (fibrogenic) function of vascular smooth muscle cells. From this time onward, low-dose colchicine (LoDoCo, 0.5 - 1.0 mg/daily) was increasingly administered orally for therapy of cardiovascular disease such as acute coronary syndromes, cardiac surgery postoperative atrial fibrillation, pericarditis, cardiac hypertrophy-associated heart failure, and systemic necrotizing vasculitis. Thus colchicine might be a new tool in the present therapeutic armamentarium for these diseases. It is simply an example of MT-disassembling drugs. Further studies will definitely be required before gaining real confidence in this kind of antitubulin therapy. This may lead to developing new and more specific antitubulins for therapy of cardiovascular disease. Biomed Rev 2017; 28: 105-110.
Keywords: microtubules, tubulin, colchicine, antitubulins, cardiovascular diseases, inflammation, fibrosis
Chaldakov GN. George E. Palade lecture. Human body as a multicrine system, with special reference to cell protein secretion: From vascular smooth muscles to adipose tissue. Biomed Rev 2016; 27:VIII-XIX.
Martınez GJ, Robertson S, Barraclough J, Xia Q, Mallat Z, Bursill C, et al. Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome. J Am Heart Assoc 2015;4:e002128. DOI: 10.1161/JAHA.115.002128.
Chaldakov GN, Deyl Z, Vankov VN. Colchicine: possible new application of its antifibrotic (antisecretory) action. Physiol Bohemoslov 1987;36:1-7.
Solak Y, Siriopol D, Yildiz A, Yilmaz MI, Ortiz A, Covic A, et al. Colchicine in renal medicine: New virtues of an ancient friend. Blood Purif 2017;43:125-135. DOI: 10.1159/000454669.
Chaldakov GN, Nikolov SD. Ultrastructure of the arterial smooth muscle cell. In: Wolf S, Werthessen NT, editors. The Smooth Muscle of the Artery. New York City, NY: Plenum Press. Adv Exp Med Biol 1975; 57:14-20.
Chaldakov G, Nikolov S, Vankov V. Fine morphological aspects of the secretory process in arterial smooth muscle cells. Part 2. Role of microtubules. Acta Morph Acad Sci Hung 1977; 25:167-174.
Chaldakov GN, Kadar A. Microtubules in arterial smooth muscle cells in vivo and in tissue culture. An electron microscope study. In: W. Hauss, R. Wissler, R. Lehman, editors. State of Prevention and Therapy of Human Arteriosclerosis and in Animal Models. Rheinisch-Westfalische Akad. Der Wissenschaften, 1978, p. 211-231.
Chaldakov GN. Antitubulins - a new therapeutic approach for atherosclerosis? Atherosclerosis 1982; 44: 385-390.
Chaldakov GN, Vankov VN. Morphological aspects of secretion in the arterial smooth muscle cell, with special reference to the Golgi complex and microtubular cytoskeleton. Atherosclerosis 1986;61:175-192. DOI: 10.1016/0021-9150(86)90137-1.
Lu Y, Chen J, Xiao M, Li W, Miller DD. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm Res 2012; 29:2943-2971. DOI: 10.1007/s11095-012-0828-z.
Chaldakov GN. Anti-inflammatory drugs and ischemic heart disease: new considerations (a cell biologist`s proposal to cardiologists). J Am Coll Cardiol 1991; 17:1445-1446.
Chaldakov GN. Proposal for clinical trials using anti-inflammatory drugs in the therapy of angina pectoris, myocardial infarction and coronary restenosis after angioplasty and bypass grafting. Med Hypotheses 1992; 37:74-75.
Chaldakov G. Colchicine in the therapy of cardiovascular disease. The Bulgraian contribution. Scr Sci Med 2017; 49(4): 84-86.
Yanev S, Fiore F, Hinev A, Ghenev PI, Hristova MG, Panayotov P, et al. From antitubulins to trackins. Biomed Rev 2016; 27: 59-67.
Robertson S, Martinez GJ, Payet CA, Barraclough JY, Celermajer DS, Bursill C, et al. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation. Clin Sci (Lond) 2016; 130:1237-1246. DOI: 10.1042/CS20160090.
Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, et al; Group CPI. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012;126: 2739-2748.
Ghenev PI, Aloe L, Panayotov P, Fiore M, Zhelyaz- kova-Savova M, Chaldakov GN. Crystal deposition diseases (crystalopathies): their relevance to colchicine therapy. (Manuscript in preparation).
Chaldakov GN, Nabika T, Nara Y, Yamori Y. Cyclic AMP- and cytochalasin B-induced arborization in cultured aortic smooth muscle cells: its cytopharmacological characterization. Cell Tissue Res 1989;255:435-442. PMID: 2538239.
Vaidya K, Arnott C, MartÃnez GJ, Ng B, McCormack S, Sullivan DR, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: A CT Coronary Angiography Study. JACC Cardiovasc Imaging 2017. DOI: 10.1016/j.jcmg.2017.08.013.
Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P. Colchicine for prevention of post-cardiac procedure atrial fibrillation: Systematic review and metaanalysis. Int J Cardiol 2017; 249:127-137. DOI: 10.1016/j.ijcard.2017.08.039.
Salih M, Smer A, Charnigo R, Ayan M, Darrat YH, Traina M, et al. Colchicine for prevention of postcardiac pro-cedure atrial fibrillation: Meta-analysis of randomized controlled trials. Int J Cardiol 2017; 243:258-262. DOI: 10.1016/j.ijcard.2017.04.022.
Hemkens LG, Ewald H, Gloy VL, Arpagaus A, Olu KK, Nidorf M, et al. Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis. Heart 2016; 102:590-596. DOI: 10.1136/heartjnl-2015-308542.
Lee JZ, Singh N, Howe CL, Low S-W, Huang JJ, Ortega G, et al.Colchicine for prevention of post-operative atrial fibrillation. J Am Coll Cardiol Clin Electrophysiol 2016; 2:78-85. DOI:10.1016/j.jacep.2015.09.016.
Campbell KB, Cicci TA, Vora AK, Burgess LD. Beyond gout: Colchicine use in the cardiovascular patient. Hosp Pharm 2015;50:859-867 DOI: 10.1310/hpj5010-859.
Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-410. DOI: 10.1016/j.jacc.2012.10.027.
Vogel RA, Forrester JS. Cooling off hot hearts: A specific therapy for vulnerable plaque? J Am Coll Cardiol 2013; 61:411-412. DOI: 10.1016/j.jacc.2012.10.026.
Alsarah A, Alsara O, Laird-Fick HS. Cardiac manifestations of Familial Mediterranean fever. Avicenna J Med 2017; 7: 158-163. DOI: 10.4103/ajm.AJM_78_17.
Antonopoulos AS, Papanikolaou E, Vogiatzi G, Oikonomou E, Tousoulis D. Anti-inflammatory agents in peripheral arterial disease. Curr Opin Pharmacol 2017; 39:1-8. DOI: 10.1016/j.coph.2017.11.001.
Akodad M, Fauconnier J, Sicard P, Huet F, Blandel F, Bourret A, et al. Interest of colchicine in the treatment of acute myocardial infarct responsible for heart failure in a mouse model. Int J Cardiol 2017; 240:347-353. DOI: 10.1016/j.ijcard.2017.03.126.
Cheng G, Kasiganesan H, Baicu CF, Wallenborn JG, Kuppuswamy D, Cooper G 4th. Cytoskeletal role in protection of the failing heart by β-adrenergic blockade. Am J Physiol Heart Circ Physiol 2012;302:H675-H687. DOI: 10.1152/ajpheart.00867.2011.
Cheng G, Takahashi M, Shunmugavel A, Wallenborn JG, DePaoli-Roach AA, Gergs Y, et al. Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem 2010; 285: 38125-38140. DOI:10.1074/jbc.M110.148650.
Dybkova N, Wagner S, Back J, Hund TJ, Mohler PJ, Sowa T, et al. Tubulin polymerization disrupts cardiac β-adrenergic regulation of late INa. Cardiovasc Res 2014;103:168-177. DOI: 10.1093/cvr/cvu120.
Chaldakov GN, Fiore M, Ghenev PI, Stankulov IS, Angellucci F, Pavlov PS, et al. Conceptual novelties in atherogenesis: Smooth muscle cells, adventitia, and adipose tissue. Biomed Rev 2000; 11: 63-67.
Ghenev PI, Kisheva AR, Chaldakov GN. Quo va dis, atherogenesis? Part 1. Smooth muscle cell se cretion - how foe becomes friend in the fight against the vulnerable atherosclerotic plaque Biomed Rev 2017; 28: 117-121.
Chaldakov GN. In: Cell Biology Textbook. Medical University Press, Varna, Bulgaria. 2014 (in Bulgarian).
Sansbury BE, Spite M. Resolution of acute inflammation and the role of resolvins in immunity, thrombosis and vascular biology. Circ Res 2016; 119(1): 113-130. DOI: 10.1161/CIRCRESAHA.116.307308
Email this article (Login required) 
