Biochim Biophys Acta. 2000 Sep 29;1468(1-2):381-95.
The interaction between lipid derivatives of colchicine and tubulin: consequences of the interaction of the alkaloid with lipid membranes.

Mons S, Veretout F, Carlier M, Erk I, Lepault J, Trudel E, Salesse C, Ducray P, Mioskowski C, Lebeau L.

Laboratoire de Synthese Bioorganique associe au CNRS, Universite Louis pasteur de Strasbourg, 67401 Illkirch, France.

Colchicine is a potent antimitotic poison which is well known to prevent microtubule assembly by binding tubulin very tightly. Colchicine also possesses anti-inflammatory properties which are not well understood yet. Here we show that colchicine tightly interacts with lipid layers. The physical and biological properties of three different lipid derivatives of colchicine are investigated parallel to those of membrane lipids in the presence of colchicine. Upon insertion in the fatty alkyl chains, colchicine rigidifies the lipid monolayers in a fluid phase and fluidifies rigid monolayers. Similarly X-ray diffraction data show that lecithin-water phases are destabilized by colchicine. In addition, an unexpectedly drastic enhancement of the photoisomerization rate of colchicine into lumicolchicine in the lipid environment is observed and further supports insertion of the alkaloid in membranes. Finally the interaction of colchicine with lipids makes the drug inaccessible to tubulin. The possible in vivo significance of these results is discussed.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11018681&dopt=Abstract colchicine



Int J Impot Res. 2000 Jun;12(3):169-75.
Treatment of Peyronie's disease with oral colchicine: long-term results and predictive parameters of successful outcome.

Kadioglu A, Tefekli A, Koksal T, Usta M, Erol H.

Department of Urology, Medical Faculty of Istanbul, University of Istanbul, Turkey. atefeknet.net.tr

As recent clinical and animal studies have indicated, colchicine, with its anti-fibrotic, anti-mitotic and anti-inflammatory activities, has suppressive effects in the pathogenesis of Peyronie's disease. Oral colchicine treatment was initiated in 60 Peyronie's patients during their acute phase (mean duration of disease: 5.7 +/- 4.3 months). Long-term results, based on changes of subjective and objective criteria, were assessed and predictive factors of successful outcome were investigated. After a mean follow-up of 10.7 +/- 4.7 months, the penile deformity improved in 30%, remained unchanged in 48.3% and deteriorated in 21.7%. Pain resolved in 95%. Best results were obtained in those with no risk factor for vascular disease, presenting during the initial 6 months of disease, degree of curvature <30 degrees, no erectile dysfunction by history and positive response to combined injection and stimulation test. In conclusion since tunica albuginea is affected as a whole in Peyronie's disease, systemic oral agents, such as colchicine, may be preferred in the early phase of the disease.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11045911&dopt=Abstract colchicine



J Mol Biol. 2000 Nov 10;303(5):679-92.
The interaction of the B-ring of colchicine with alpha-tubulin: a novel footprinting approach.

Chaudhuri AR, Seetharamalu P, Schwarz PM, Hausheer FH, Luduena RF.

Department of Biochemistry, University of Texas Health Science Center at San Antonio, TX 78229, USA. asisioc09.uthscsa.edu

Tubulin, the major structural component of the microtubules, participates actively in mitotic spindle formation and chromosomal organization during cell division. Tubulin is the major target for a variety of anti-mitotic drugs. Some of the drugs, such as Vinca alkaloids and taxol, are routinely used for cancer chemotherapy. It is unfortunate that our knowledge of the binding sites on tubulin of these drugs is limited because of lack of a useful and appropriate tool. The photoaffinity labeling approach is the major technique available at present to detect the binding sites of drugs on tubulin. This method, however, has several limitations. First, only part of the binding site can be identified, namely, the residues which react with the photoaffinity label. Second, there are regions of tubulin which are not at the binding site but are affected by the binding of the drug; these regions can not be detected by the photoaffinity labeling approach. The third, and perhaps most serious, limitation is that the traditional approach can detect areas which have nothing to do with the binding of the ligand but which are within a certain distance of the binding site, that distance being less than the length of the photoreactive moiety attached to the ligand. There has been a great deal of controversy on the localization of the binding site of colchicine on tubulin, with some reports suggesting that the binding site is on alpha and some supporting a binding site on beta. Colchicine also has significant effects on tubulin conformation, but the regions which are affected have not been identified. We have attempted here to address these questions by a novel "footprinting" method by which the drug-binding sites and as well as the domain of tubulin affected by drug-induced conformational changes could be determined. Here, we report for the first time that the interaction of the B-ring of colchicine with the alpha-subunit affects a domain of tubulin which appears to be far from its binding site. This domain includes the cysteine residues at positions 295, 305, 315 and 316 on alpha-tubulin; these residues are located well away from the alpha/beta interface where colchicine appears to bind. This is correlated with the stabilizing effect of colchicine on the tubulin molecule. Furthermore, we also found that the B-ring of colchicine plays a major role in the stability of tubulin while the A and the C-rings have little effect on it. Our results therefore, support a model whereby colchicine binds at the alpha/beta interface of tubulin with the B-ring on the alpha-subunit and the A and the C-rings on the beta-subunit. 2000 Academic Press.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11061968&dopt=Abstract colchicine



Biochim Biophys Acta. 2000 Nov 15;1502(3):351-62.
Antioxidant properties of colchicine in acute carbon tetrachloride induced rat liver injury and its role in the resolution of established cirrhosis.

Das D, Pemberton PW, Burrows PC, Gordon C, Smith A, McMahon RF, Warnes TW.

The Liver Unit, Manchester Road Infirmary, Manchester, UK.

Antioxidant and antifibrotic properties of colchicine were investigated in the carbon tetrachloride (CCl(4)) rat model. (1) The protective effect of colchicine pretreatment on CCl(4) induced oxidant stress was examined in rats subsequently receiving a single lethal dose of CCl(4). Urinary 8-isoprostane, kidney and liver malondialdehyde and kidney glutathione levels increased following CCl(4) treatment, but only the rise in kidney malondialdehyde was significantly inhibited by colchicine pretreatment. Serum total antioxidant levels were significantly higher in the colchicine pretreatment group. (2) The long term effects of colchicine treatment on CCl(4) induced liver damage were investigated using liver histology and biochemical markers (hydroxyproline and type III procollagen peptide). Co-administration of colchicine with sub-lethal doses of CCl(4) over 10 weeks did not prevent progression to cirrhosis. However, rats made cirrhotic with repeated CCl(4) challenge and subsequently treated with colchicine for 12 months, all showed histological regression of cirrhosis. (3) The antioxidant effect of colchicine in vitro was evident only at very high concentrations compared to other plasma antioxidants. In summary, colchicine has only weak antioxidant properties, but does afford some protection against oxidative stress; more importantly, long term treatment with this drug may be of value in producing regression of established cirrhosis.


Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11068178&dopt=Abstract colchicine