Home About us Contact | |||
Microtubule Polymerization (microtubule + polymerization)
Selected AbstractsTreatment of pediculosis capitis with thiabendazole: a pilot studyINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 12 2003Mohammad Reza Namazi MD Background, Despite the improvement of health standards, head lice infestation remains a problem worldwide. In addition, there is increasing evidence that head lice are becoming resistant to common pediculocides. Aim, To test the potential effectiveness of thiabendazole, a potent and broad-spectrum antiparasitic and scabicidal agent, for the treatment of pediculosis capitis. Methods, Twenty-three female patients, aged 7,12 years, who had active head lice infestation, were treated with oral thiabendazole, 20 mg/kg twice daily for 1 day, with repeat treatment after 10 days. Results, On the 11th day, meticulous hair examination showed that 21 patients had responded to treatment [91%; 95% confidence interval (CI), 71,98%], with 14 showing complete responsiveness (61%; 95% CI, 40,78%). The only adverse reactions observed were nausea and mild dizziness, which occurred in four patients, three of whom took the drug on an empty stomach. Conclusions, Thiabendazole may be a promising treatment for head lice infestation. The primary action of this drug seems to be the inhibition of parasite microtubule polymerization by binding to ,-tubulin. In addition, thiabendazole may interfere with the synaptic transmission of lice through its probable cholinergic effect. As pediculosis capitis is a very communicable disease, the unresponsiveness to thiabendazole could largely be attributed to new infestations during the drug-free interval. Therefore, massive and simultaneous rather than individual and isolated treatments should be used to achieve the epidemiologic control of this ectoparasitosis. As this is a preliminary study, the performance of double-blind, randomized controlled trials on this subject is warranted. Thiabendazole, either alone or in combination with other agents, may prove to be of particular use in areas in which head lice show resistance to common pediculocides. [source] Characterization of the Interaction of TZT-1027, a Potent Antitumor Agent, with TubulinCANCER SCIENCE, Issue 7 2000Tsugitaka Natsume TZT-1027, a derivative of dolastatin 10 isolated from the Indian Ocean sea hare Dolabella auricularia in 1987 by Pettit et al., is a potent antimicrotubule agent. We have compared the activity of TZT-1027 with that of dolastatin 10 as well as the vinca alkaloids vinblastine (VLB), vincristine (VCR) and vindesine (VDS). TZT-1027 and dolastatin 10 inhibited microtubule polymerization concentration-dependently at 1,100 ,M with IC50 values of 2.2±0.6 and 2.3±0.7 ,M, respectively. VLB, VCR and VDS inhibited microtubule polymerization at 1,3 ,M with IC50 values of 2.7±0.6, 1.6±0.4 and 1.6±0.2 ,M, respectively, but showed a slight decrease in inhibitory effect at concentrations of 10 ,M or more. TZT-1027 also inhibited monosodium glutamate-induced tubulin polymerization concentration-dependently at 0.3,10 ,M, with an IC50 of 1.2 ,M, whereas VLB was only effective at 0.3,3 ,M, with an IC50 of 0.6 ,M, and caused so-called "aggregation" of tubulin at 10 ,M. Scatchard analysis of the binding data for [3H]VLB suggested one binding site (Kd 0.2±0.04 ,M and Bmax 6.0±0.26 nM/mg protein), while that for [3H]TZT-1027 suggested two binding sites, one of high affinity (Kd 0.2±0.01 ,M and Bmax 1.7±0.012 nM/mg protein) and the other of low affinity (Kd 10.3±1.46 ,M, and Bmax 11.6±0.83 nM/mg protein). [3H]TZT-1027 was completely displaced by dolastatin 10 but only incompletely by VLB. [3H]VLB was completely displaced by dolastatin 10 and TZT-1027. Furthermore, TZT-1027 prevented [3H]VLB from binding to tubulin in a non-competitive manner according to Lineweaver-Burk analysis. TZT-1027 concentrationdependently inhibited both [3H]guanosine 5,-triphosphate (GTP) binding to and GTP hydrolysis on tubulin. VLB inhibited the hydrolysis of GTP on tubulin concentration-dependently to a lesser extent than TZT-1027, but no inhibitory effect of VLB on [3H]GTP binding to tubulin was evident even at 100 ,M. Thus, TZT-1027 affected the binding of VLB to tubulin, but its binding site was not completely identical to that of VLB. TZT-1027 had a potent inhibitory effect on tubulin polymerization and differed from vinca alkaloids in its mode of action against tubulin polymerization. [source] Curcumin disrupts meiotic and mitotic divisions via spindle impairment and inhibition of CDK1 activityCELL PROLIFERATION, Issue 4 2010A. Bielak-Zmijewska Objectives:, Curcumin, a natural compound, is a potent anti-cancer agent, which inhibits cell division and/or induces cell death. It is believed that normal cells are less sensitive to curcumin than malignant cells; however, the mechanism(s) responsible for curcumin's effect on normal cells are poorly understood. The aim of this study was to verify the hypothesis that curcumin affects normal cell division by influencing microtubule stability, using mouse oocyte and early embryo model systems. Materials and methods:, Maturating mouse oocytes and two-cell embryos were treated with different concentrations of curcumin (10,50 ,m), and meiotic resumption and mitotic cleavage were analysed. Spindle and chromatin structure were visualized using confocal microscopy. In addition, acetylation and in vitro polymerization of tubulin, in the presence of curcumin, were investigated and the damage to double-stranded DNA was studied using ,H2A.X. CDK1 activity was measured. Results and conclusions:, We have shown for the first time, that curcumin, in a dose-dependent manner, delays and partially inhibits meiotic resumption of oocytes and inhibits meiotic and mitotic divisions by causing disruption of spindle structure and does not induce DNA damage. Our analysis indicated that curcumin affects CDK1 kinase activity but does not directly affect microtubule polymerization and tubulin acetylation. As our study showed that curcumin impairs generative and somatic cell division, its future clinical use or of its derivatives with improved bioavailability after oral administration, should take into consideration the possibility of extensive side-effects on normal cells. [source] A High-Content, Cell-Based Screen Identifies Micropolyin, A New Inhibitor of Microtubule DynamicsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2009Manu De Rycker High-content cell-based screens provide a powerful tool to identify new chemicals that interfere with complex biological processes. Here, we describe the identification of a new inhibitor of microtubule dynamics (micropolyin) using a high-content screen. Integrated high-resolution imaging allowed for fast selection of hits and progression to target identification. Treatment of cells with micropolyin efficiently causes a pro-metaphase arrest, with abnormal spindle morphology and with the spindle assembly checkpoint activated. The arrest appears to result from interference of micropolyin with microtubule dynamics. We show in vitro that tubulin is indeed the target of micropolyin and that micropolyin inhibits microtubule polymerization. Our results demonstrate the power of high-content image- and cell-based screening approaches to identify potential new drug candidates. As our approach is unbiased, it should allow for discovery of new targets that may otherwise be overlooked. [source] |