Reference

Suppression of Microtubule Dynamics by Epothilone B Is Associated with Mitotic Arrest

Suppression of Microtubule Dynamics by Epothilone B Is Associated with Mitotic Arrest. Kamath, Kathy; Jordan, Mary Ann (Department of Molecular Cellular and Developmental Biology and the Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA). Cancer Research, 63(18), 6026-6031 (English) 2003 American Association for Cancer Research. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The epothilones are a group of novel microtubule-targeted, antimitotic compds. that have a paclitaxel-like, assembly enhancing effect on tubulin in vitro as well as in cultured cells. We hypothesize that epothilones induce mitotic arrest by suppressing microtubule dynamics. To test this hypothesis, we used MCF7 cells stably transfected with GFP-a-tubulin to analyze microtubule dynamics at three concns. of epothilone B, one that induced no mitotic arrest (0.2 nM, 20 h), one that induced one-third maximal mitotic arrest (IC33, 2 nM, 20 h), and one that induced half-maximal mitotic arrest (IC50, 3.5 nM, 20 h). We found that epothilone B suppressed microtubule dynamics in a concn.-dependent manner coincident with mitotic block. At 0.2 nM epothilone B, dynamics were not significantly altered. At 2 nM epothilone B (IC33), the mean growth and shortening rates were decreased by 38 and 27%, resp. Dynamicity was decreased by 47%. At the IC50, 80% of the cells had nearly complete stabilization of microtubule dynamics, and no anaphase or telophase figures were obsd. Comparison of the effects of epothilone B on microtubule dynamics with those of paclitaxel indicated that both drugs alter the same microtubule dynamic parameters to a similar extent. At the IC50 for mitotic arrest, dynamicity was reduced by 54% by paclitaxel compared with 62% for epothilone B.In this experiment, several chemicals are used like 152044-54-7 In 65% of the cells treated with paclitaxel, the microtubules were completely stabilized. Thus, the effects of epothilone B on microtubule dynamics are remarkably similar to those of paclitaxel, suggesting that both drugs induce mitotic block by a similar mechanism. .

Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol)

Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). Kowalski, Richard J.; Giannakakou, Parasekevi; Hamel, Ernest (NCI, Frederick Cancer Research Development Center, Frederick, MD 21702, USA). Journal of Biological Chemistry, 272(4), 2534-2541 (English) 1997 American Society for Biochemistry and Molecular Biology. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Epothilones A and B, natural products with minimal structural analogy to taxoids, have effects similar to those of paclitaxel (Taxol?) in cultured cells and on microtubule protein, but differ from paclitaxel in retaining activity in multidrug-resistant cells. We examd. interactions of the epothilones with purified tubulin and addnl. cell lines, including a paclitaxel-resistant ovarian carcinoma line with an altered b-tubulin. The epothilones, like paclitaxel, induced tubulin to form microtubules at low temps. and without GTP and/or microtubule-assocd. proteins. The epothilones are competitive inhibitors of the binding of [3H]paclitaxel to tubulin polymers.Several substances with their cas registry numbers 33069-62-4 and 152044-54-7 may be metioned in this study. The apparent Ki values for epothilones A and B were 1.4 and 0.7 mM by Hanes anal. and 0.6 and 0.4 mM by Dixon anal. In the paclitaxel-sensitive human cell lines we examd., epothilone B had greater antiproliferative activity than epothilone A or paclitaxel, while epothilone A was usually less active than paclitaxel. A multidrug-resistant colon carcinoma line and the paclitaxel-resistant ovarian line retained sensitivity to the epothilones. With Potorous tridactylis kidney epithelial (PtK2) cells examd. by indirect immunofluorescence, microtubule bundles appeared more rapidly following epothilone B treatment, and there were different proportions of various mitotic aberrations following treatment with different drugs. .