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Volumn 10, Issue 1, 1998, Pages 123-130

Microtubules and actin filaments: Dynamic targets for cancer chemotherapy

Author keywords

[No Author keywords available]

Indexed keywords

ACTIN; ANTIMITOTIC AGENT; BETA TUBULIN; BISTHEONELLIDE A; CRYPTOPHYCIN; CYTOCHALASIN; DISCODERMOLIDE; EPOTHILONE A; JASPAMIDE; NATURAL PRODUCT; ONCOPROTEIN; ONCOPROTEIN 18; PACLITAXEL DERIVATIVE; UNCLASSIFIED DRUG;

EID: 0032006059     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(98)80095-1     Document Type: Article
Times cited : (622)

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    • of special interest. In this paper the authors demonstrate taxol-induced phosphorylation and activation of the Raf-1 mitogen-stimulated protein kinase, coincident with phosphorylation of bcl-2. Depletion of Raf-1 protein by benzoquinone ansamycin GA prevented taxol-induced apoptosis and bcl-2 phosphorylation.
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    • of special interest. Here, it is reported that to taxol, vinca alkaloids, colchicine, epothilones and other microtubule active agents induce Raf-1/bcl-2 phosphorylation.
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    • of special interest. In this paper evidence is presented showing that taxol, but not nocodazole, at micromolar concentrations, may induce a G1 block from which nontransformed rat and human fibroblasts recover and proliferate after release from taxol; however, transformed cells of the same lineage slip through the checkpoint and undergo apoptotis. The results suggest the existence of a microtubule-dependent checkpoint in G1 which is abrogated in transformed cells.
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    • of special interest. This group found that normal mouse and human fibroblasts arrested with a 4N DNA content when treated with nocodazole and Colcemid, whereas isogeneic p53-deficient or pRb-deficient derivatives became polyploid indicating different susceptibilities of normal and mutated cells to anti-mitotic drugs.
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    • of special interest. Here the authors report that adding taxol and vinorelbine, a synthetic vinca alkaloid, at low nanomolar concentrations concurrently to cultures of human melanoma cell lines, resulted in supra-additive or synergistic antiproliferative effects.
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    • of special interest. In this report the authors report that microtubules composed of purified αβ III or αβIV bovine brain tubulin were sevenfold less sensitive to the suppressive effects of bound taxol on the rate of shortening during excursions of dynamic instability, suggesting that cellular expression of increased levels of βIII or βIV tubulin isotypes may be an important mechanism of tumor cell resistance to taxol.
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    • In this report the authors observed that taxol-resistant human ovarian tumors displayed significant increases in expression of class I, III and IVa β-tubulins, when compared to untreated primary ovarian tumors. Taxol-resistant cultured human lung cancer cells are also showed increases in the levels of classes, I,II,III, and IVa β tubulins, although MDR expression, total tubulin levels, and drug.
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    • of special interest. The authors of this paper report that human prostate carcinoma cells (DU145), selected for resistance to estramustine, were moderately cross-resistant to paclitaxel, and overexpressed two β-tubulin isotypes three- to fourfold (classes IVa and III), suggesting that altered expression of tubulin isotypes may play a role in cellular resistance to antimicrotubule drugs.
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    • Resistance mechanisms in human sarcoma mutants derived by single-step exposure to paclitaxel (Taxol)
    • of special interest. In this report single-step exposure of MES-SA sarcoma cells to paclitaxel induced formation of 5 Mdr1-negative clones that were resistant to taxol, cross-resistant to vinca alkaloids, and underexpressed 2 β-tubulin isotypes, β5 (class IVa) and β4 (class III), as determined by RT-PCR, which suggests that altered microtubule function is responsible for resistance to taxol in these cells.
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    • of outstanding interest. Here, the authors report that purified tubulin from two taxol-resistant sublines of human ovarian carcinoma cells exhibited resistance to taxol-induced polymerization which was attributed to acquired point mutations in the M40 isotype. The cell lines were sensitive to vinblastine, accumulated paclitaxel equally with the parental cells, expressed no detectable MDR-1 RNA, and expressed β-tubulin isotypes similarly, with a 1-5-fold increase in expression of M40 (betal) RNA.
    • Giannakakou P, Sackett D, Kang Y, Zhan Z, Buters J, Fojo T, Poruchynsky M. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. of outstanding interest J Biol Chem. 272:1997;17118-17125 Here, the authors report that purified tubulin from two taxol-resistant sublines of human ovarian carcinoma cells exhibited resistance to taxol-induced polymerization which was attributed to acquired point mutations in the M40 isotype. The cell lines were sensitive to vinblastine, accumulated paclitaxel equally with the parental cells, expressed no detectable MDR-1 RNA, and expressed β-tubulin isotypes similarly, with a 1-5-fold increase in expression of M40 (betal) RNA.
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    • The microtubule-destabilizing activity of metablastin (p19) is controlled by phosphorylation
    • of special interest. In this experiment, microinjection of recombinant Op18 induced disassembly of microtubules in cells and in vitro. Aspartate substitution of a single serine residue (Ser63) abolished the effect on cellular microtubules.
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    • of special interest. This report documents the purification of OP18 from calf thymus extracts and the finding that it is a 17 kDa protein that it appears to bind tubulin dimers; destabilize microtubules, increase their catastrophe rates and decrease their growth rates. OP18 inhibited the taxol (300 μM)-induced polymerization of microtubules. OP18 is therefore a plausible regulator of microtubule dynamics during the cell cycle.
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    • of special interest. In this paper it is reported that increased expression of Op 18 resulted in microtubule depolymerization in interphase cells, but mitotic spindles were normal. Expression of Op18 mutated at serines 25 and 38 resulted in an absence of mitotic microtubules.
    • Marklund U, Larsson N, Graden H, Brattsand G, Gullberg M. Oncoprotein 18 is a phosphorylation-responsive regulator of microtubule dynamics. of special interest EMBO J. 15:1996;5290-5298 In this paper it is reported that increased expression of Op 18 resulted in microtubule depolymerization in interphase cells, but mitotic spindles were normal. Expression of Op18 mutated at serines 25 and 38 resulted in an absence of mitotic microtubules.
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    • 2+/calmodulin-dependent kinase IV/Gr can suppress the microtubule regulating activity of Op18. Increased phosphorylation of Op 18 on serine residue 16 is associated with partial degradation of Op18 and an increase in cellular microtubule mass.
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