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Identification and characterization of a new tubulin-binding tetrasubstituted brominated pyrrole.
Mooberry SL, Weiderhold KN, Dakshanamurthy S, Hamel E, Banner EJ, Kharlamova A, Hempel J, Gupton JT, Brown ML
(2007) Mol Pharmacol 72: 132-40
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Agents, Cell Cycle, Colchicine, Drug Resistance, Neoplasm, Microtubules, Models, Molecular, Phosphorylation, Poly(ADP-ribose) Polymerases, Proto-Oncogene Proteins c-bcl-2, Pyrroles, Tubulin
Show Abstract · Added September 16, 2013
We studied the mechanism of action of 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (JG-03-14) and found that it is a potent microtubule depolymerizer. JG-03-14 caused a dose-dependent loss of cellular microtubules, formation of aberrant mitotic spindles, accumulation of cells in the G(2)/M phase of the cell cycle, and Bcl-2 phosphorylation. These events culminated in the initiation of apoptosis, as evidenced by the caspase 3-dependent cleavage of poly(ADP-ribose) polymerase (PARP). JG-03-14 has antiproliferative activity against a wide range of cancer cell lines, with an average IC(50) value of 62 nM, and it is a poor substrate for transport by P-glycoprotein. JG-03-14 inhibited the polymerization of purified tubulin in vitro, consistent with a direct interaction between the compound and tubulin. JG-03-14 potently inhibited the binding of [(3)H]colchicine to tubulin, suggesting that it bound to tubulin at a site overlapping the colchicine site. JG-03-14 had antitumor effects in the PC3 xenograft model, in which it caused greater than 50% reduction in tumor burden after 14 days of treatment. Molecular modeling studies indicated that the dimethoxyphenyl group of JG-03-14 occupies a space similar to that of the trimethoxyphenyl group of colchicine. However, the 2,3,5-trisubstituted pyrrole group, which is connected to the dimethoxyphenyl moiety, interacted with both alpha and beta tubulin in space not shared with colchicine, suggesting significant differences compared with colchicine in the mechanism of binding to tubulin. Our results suggest that this tetransubstituted pyrrole represents a new, biologically active chemotype for the colchicine site on tubulin.
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12 MeSH Terms
A-204197, a new tubulin-binding agent with antimitotic activity in tumor cell lines resistant to known microtubule inhibitors.
Tahir SK, Han EK, Credo B, Jae HS, Pietenpol JA, Scatena CD, Wu-Wong JR, Frost D, Sham H, Rosenberg SH, Ng SC
(2001) Cancer Res 61: 5480-5
MeSH Terms: Antineoplastic Agents, Apoptosis, Binding Sites, Cell Cycle, Cell Cycle Proteins, Cell Division, Colchicine, Drug Interactions, Drug Resistance, Multiple, G2 Phase, Humans, Microtubules, Mitosis, Oxadiazoles, Paclitaxel, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Time Factors, Tubulin, Tumor Cells, Cultured, Vinblastine
Show Abstract · Added February 15, 2016
Drug resistance is a prevalent problem in the treatment of neoplastic disease, and the effectiveness of many clinically useful drugs is limited by the fact that they are substrates for the efflux pump, P-glycoprotein. Because there is a need for new compounds that are effective in treating drug-resistant tumors, we tested A-204197 (4-[4-acetyl-4,5-dihydro-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-N,N-dimethylbenzeneamine), a novel oxadiazoline derivative with antiproliferative properties, on cell lines that were either sensitive or resistant to known microtubule inhibitors. Cell lines that were resistant to paclitaxel, vinblastine, or colchicine were equally sensitive to A-204197 (proliferation IC50s ranging from 36 to 48 nM) despite their expression levels of P-glycoprotein. The effect of A-204197 on cell growth was associated with cell cycle arrest in G2-M, increased phosphorylation of select G2-M checkpoint proteins, and apoptosis. In competition-binding assays, A-204197 competed with [3H]-labeled colchicine for binding to tubulin (K(i) = 0.75 microM); however, it did not compete with [3H]-labeled paclitaxel. A-204197 prevented tubulin polymerization in a dose-dependent manner (IC50 = 4.5 microM) in vitro and depolymerized microtubules in a time-dependent manner in cultured cells. These findings indicate A-204197 is a promising new tubulin-binding compound with antimitotic activity that has potential for treating neoplastic diseases with greater efficacy than currently used antimitotic agents.
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21 MeSH Terms
Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation.
Tateishi T, Soucek P, Caraco Y, Guengerich FP, Wood AJ
(1997) Biochem Pharmacol 53: 111-6
MeSH Terms: Colchicine, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Gout Suppressants, Humans, Microsomes, Liver
Show Abstract · Added March 5, 2014
Colchicine disposition involves both active biliary and renal excretion of parent drug, and at least in mammals a substantial fraction undergoes hepatic demethylation prior to excretion. We investigated the biotransformation of [3H]colchicine in a panel of microsomal preparations obtained from sixteen human liver samples. The production rate of the main metabolites of colchicine's 3-demethylcolchicine (3DMC) and 2-demethylcolchicine (2DMC), was linear in relation to incubation time, cytochrome (P450) content, and substrate concentration. Following the incubation of colchicine (5 nM) with microsomes in the presence of an NADPH-generating system for 60 min, 9.8% and 5.5% of the substrate were metabolized to 3DMC and 2DMC, respectively. The formation rate of colchicine metabolites exhibited a marked variation between the different microsomal preparations. The formation rates of both colchicine metabolites were correlated significantly with nifedipine oxidase activity, a marker of CYP3A4 activity (r = 0.96, P < 0.001), but not with the metabolic markers of CYP2A6, CYP2C19, CYP2C9, CYP2D6, and CYP2E1 activities. Chemical inhibition of CYP3A4 by preincubation with gestodene (40 microM) or troleandomycin (40 microM) reduced the formation of 3DMC and 2DMC by 70 and 80%, respectively, whereas quinidine, diethyldithiocarbamate, and sulfaphenazole had no inhibitory effect. Similarly, antibodies raised against CYP3A4 almost completely abolished colchicine demethylation and nifedipine oxidase activity, but preimmune IgG had no effect. In conclusion, colchicine was metabolized to 3DMC and 2DMC by human liver microsomes. The production of colchicine metabolites was mediated by CYP3A4, and its rate varied greatly between microsomal preparations obtained from different liver samples. The coadministration of colchicine with known inhibitors or substrates of CYP3A4 may inhibit colchicine metabolism, resulting in concentration-related toxicity.
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6 MeSH Terms
Inactivation of L-type Ca channels in embryonic chick ventricle cells: dependence on the cytoskeletal agents colchicine and taxol.
Galli A, DeFelice LJ
(1994) Biophys J 67: 2296-304
MeSH Terms: Animals, Biophysical Phenomena, Biophysics, Calcium Channels, Chick Embryo, Colchicine, Cytoskeleton, Heart Ventricles, In Vitro Techniques, Kinetics, Models, Biological, Paclitaxel
Show Abstract · Added February 19, 2015
This article shows that colchicine and taxol strongly influence the kinetics of L-type Ca channels in intact cardiac cells, and it suggests a mechanism for this action. It is known that colchicine disassociates microtubules into tubulin, and that taxol stabilizes microtubules. We have found that colchicine increases the probability that Ca channels are in the closed state and that taxol increases the probability they are in the open state. Moreover, taxol lengthens the mean open time of Ca channels. In this regard, taxol is similar to Bay-K 8644; however, Bay K works on inside-out patches, but taxol does not. Neither colchicine nor taxol alters the number of Ca channels in a patch. We have quantified these results as follows. It is known that L-type channels in embryonic chick heart ventricle cells have voltage- and current-dependent inactivation. In 10 mM Ba, channel conductance is linear in the range -10 to 20 mV. The conductance is 12 +/- 1 pS, and the extrapolated reversal potential is 42 +/- 2 mV (n = 3). In cell-attached patches, inactivation depends on the number of channels. One channel (holding at -80 mV and stepping to 0 mV for 500 ms) shows virtually no inactivation. However, three channels inactivate with a time constant of 360 +/- 20 ms (n = 6). In similar patches, colchicine (80 microM for 15 min) decreases the inactivation time constant to 162 +/- 33 ms (n = 4) and taxol (50 microM for 10 min) virtually abolishes inactivation (time constant 812 +/- 265 ms (n = 4)). We suggest that colchicine and taxol affect Ca channels through their action on the cytoskeleton, which in turn regulates the effective concentration of inactivating ions near the mouths of channels. An alternate explanation is that free tubulin interacts directly with Ca channels.
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12 MeSH Terms
Microtubule assembly is altered following covalent modification by the n-hexane metabolite 2,5-hexanedione.
Boekelheide K, Eveleth J, Neely MD, Sioussat TM
(1991) Adv Exp Med Biol 283: 433-42
MeSH Terms: Anilino Naphthalenesulfonates, Animals, Binding Sites, Cattle, Colchicine, Hexanes, Hexanones, In Vitro Techniques, Microtubules, Temperature, Tubulin
Added September 13, 2014
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11 MeSH Terms