Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations.

Jordan, Mary Ann; Toso, Robert; Thrower, Douglas; Wilson, Leslie

doi:10.1073/pnas.90.20.9552

Cited by 982 publications

(796 citation statements)

References 21 publications

(18 reference statements)

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“…After 8 days of paclitaxel treatment a 50% cell survival was observed for a paclitaxel concentration of 0.9 nM whereas an 80% cell survival was found after a 16 h exposure (Figure 9b). A time-dependent intracellular accumulation of paclitaxel could account for these variations (Jordan et al, 1993). Paclitaxel treatment of MCF-7 cells not only leads to an accumulation of cells with a G2/M DNA content, but also increases p21 in this phase of the cell cycle, suggesting that the increase in p21 may be the cause or the consequence of the paclitaxel-induced cell cycle block.…”

Section: In¯uence Of Antisense-p21 On Cell Survival After Paclitaxel mentioning

confidence: 99%

Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line

et al. 1997

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It has been shown recently that expression of p21 is enhanced by paclitaxel. This cytotoxic compound induces mitotic spindle damage resulting in blockade of the mitotic cell cycle associated or not with apoptotic cell death. In the present study, we showed that, in MCF-7 cells, paclitaxel induced accumulation of p21 in cells with a G2/M DNA content, corresponding to cells either in abnormal mitosis or in an interphase-like state (decondensed chromatin) with multiple nuclei. In MCF-7 cells, the increase in p21 was subsequent to the mitotic arrest and was associated with the exit from abnormal mitosis leading to formation of cells with micronuclei. In this cell line, we noted a relationship between the elevation of p21 expression and the inhibition of p34 cdc2 activity. High levels of p21 protein were also found to be associated with inactive p34 cdc2 /cyclin B protein complex after treatment with paclitaxel. Treatment with p21 antisense oligonucleotide partially blocked induction of p21 expression by paclitaxel and signi®cantly reduced survival of MCF-7 cells exposed to this agent. In NIH-OVCAR-3 cells, which are de®cient in basal and paclitaxel-induced p21 expression, paclitaxel led to a prolonged activation of p34 cdc2 and a delayed mitotic exit associated with apoptotic cell death. These observations suggest that p21 is not required for the mitotic arrest in response to paclitaxel, but argue in favor of a role for this inhibitor in facilitating the exit from abnormal mitosis. This e ectively enhances cell survival after paclitaxel-induced spindle damage.

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Section: In¯uence Of Antisense-p21 On Cell Survival After Paclitaxel mentioning

confidence: 99%

Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line

et al. 1997

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“…taxel seems to block mitosis mainly by stabilizing spindle microtubules, while abnormal binding of microtubule polymers is seen at higher concentrations as a result of paclitaxel's stabilizing and promoting characteristics (Jordan et al, 1993). This is in contrast to agents, such as colchicine and vinblastine, that inhibit microtubule assembly.…”

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confidence: 96%

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Terzis

Thorsen²,

Heese³

et al. 1997

Br J Cancer

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Summary Paclitaxel (Taxol), an anti-cancer drug derived from Taxus species, was tested for its anti-migrational, anti-invasive and antiproliferative effect on two human glioma cell lines (GaMg and D-54Mg) grown as multicellular tumour spheroids. In addition, the direct effect of paclitaxel on glioma cells was studied using flow cytometry and scanning confocal microscopy. Both cell lines showed a dose-dependent growth and migratory response to paclitaxel. The GaMg cells were found to be 5-10 times more sensitive to paclitaxel than D-54Mg cells. Paclitaxel also proved to be remarkably effective in preventing invasion in a co-culture system in which tumour spheroids were confronted with fetal rat brain cell aggregates. Control experiments with Cremophor EL (the solvent of paclitaxel for clinical use) in this study showed no effect on tumour cell migration, cell proliferation or cell invasion. Scanning confocal microscopy of both cell lines showed an extensive random organization of the microtubules in the cytoplasm. After paclitaxel exposure, the GaMg and the D-54Mg cells exhibited a fragmentation of the nuclear material, indicating a possible induction of apoptosis. In line with this, flow cytometric DNA histograms showed an accumulation of cells in the G/M phase of the cell cycle after 24 h of paclitaxel exposure. After 48 h, a deterioration of the DNA histograms was observed indicating nuclear fragmentation.

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“…Vinca alkaloids such as vinblastine can bind both to soluble tubulin dimers and microtubules and, at high concentrations, inhibit microtubule polymerization (Jordan et al, 1992;Lobert et al, 1996;Nagan et al, 2000). Taxanes, such as paclitaxel and the related compound docetaxel, only bind to polymerized tubulin and promote microtubule polymerization (Jordan et al, 1993;Liu et al, 1994). At clinically achievable concentrations, both vincas and taxanes induce apoptotic cell death by inhibiting microtubule dynamics, without altering the percentage of tubulin polymerization.…”

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confidence: 99%

Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity

et al. 2001

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SummaryThe present study was performed to gain insight into the role of p53 on the cytotoxicity of tubulin-binding agents (TBA) on cancer cells. Drug sensitivity, cell cycle distribution and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the MN-1 cell line containing wild-type p53 (wt-p53) and the MDD2 line, containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to the cytotoxic effects of vinblastine and paclitaxel than the MN1 cell line. MN1 cells, but not MDD2 cells, displayed wt-p53 protein accumulation as well as p21/WAF1 and cyclin G1 induction after exposure to TBA. Both cell lines arrested at G 2 /M after drug treatment. However exposure of MN1 cells to TBA resulted in a stronger variation in mitochondrial membrane potential, associated with cleavage of PARP, and more apoptosis, as measured by annexin V expression. After exposure to vinblastine, Raf 1 kinase activity was reduced in MDD2 cells but not in MN1 cells. Addition of flavopiridol to vinblastine-and paclitaxel-treated cells reversed the MDD2-resistant phenotype by inducing G 1 cell cycle arrest and inhibiting endoreduplication. We conclude that the p53 status of cancer cells influences their sensitivity to TBA cytotoxicity. This effect is likely to involve differences in the apoptotic cascade.

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Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations.

Cited by 982 publications

References 21 publications

Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line

Involvement of p21 in mitotic exit after paclitaxel treatment in MCF-7 breast adenocarcinoma cell line

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent cytotoxicity

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