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Delayed expression of apoptosis in human lymphoma cells undergoing low-dose taxol-induced mitotic stress
R Allman1, R J Errington, P J Smith
1Cancer Research Wales Laboratories, Velindre NHS Trust, Whitchurch, Cardiff CF14 2TL, Wales, UK. Richard.Allman@velindre-tr.wales.nhs.uk
Abstract:
The links between low-dose range taxol-induced mitotic arrest and the subsequent engagement of apoptosis are important for identifying the routes to therapeutic action. Here we have investigated the timing of cell-cycle perturbation and cell death responses following continuous exposure to clinically relevant drug concentrations (1-20 nM). Following 8 h of exposure to taxol, the cell line DoHH2 (p53 wild type) exhibited mitotic arrest and engagement of apoptosis, whereas the cell line SU-DHL-4 (p53 mutant) breached cell-cycle arrest with progression to an abnormal cycle and a 24 h delay in the engagement of apoptosis. Imaging showed equivalent dysfunction of mitotic spindles in both cell lines. The results of kinetic analyses indicated that although cell death may occur at different stages of progression through mitosis and subsequent cell cycles, the overall kinetics of cell death relate to the rate of arrival at a critical event window in the cell cycle. We propose a simple model of low-dose taxol-induced cell death for cycling populations in which mitotic stress acts as a primary trigger for apoptosis with equivalent but potentially delayed outcomes. This view provides a rationale for the clinical effectiveness of this agent, independent of the initial capacity of the tumour cell to engage apoptosis due, for example, to mutant p53 expression. The results provide a perspective for the design of combination regimens that include low-dose taxol and a component that may disturb mitotic delivery.
Insights
Low-dose taxol causes mitotic arrest and apoptosis. Cell death timing varies with p53 status, but mitotic stress consistently triggers cell death, supporting taxol
Area of Science:
- Cell Biology
- Pharmacology
- Cancer Research
Background:
- Understanding taxol's mechanism of action at low doses is crucial for cancer therapy.
- The relationship between taxol-induced mitotic arrest and apoptosis is key to its therapeutic effects.
- p53 status influences cellular responses to chemotherapy, including taxol.
Purpose of the Study:
- To investigate the temporal dynamics of cell-cycle perturbation and apoptosis following low-dose taxol exposure.
- To compare the responses of p53 wild-type and p53 mutant cancer cell lines to taxol.
- To model the kinetics of low-dose taxol-induced cell death in cycling cell populations.
Main Methods:
- Continuous exposure of DoHH2 (p53 wild type) and SU-DHL-4 (p53 mutant) cell lines to clinically relevant taxol concentrations (1-20 nM).
- Cell-cycle analysis to assess mitotic arrest and progression.
- Apoptosis assays to quantify programmed cell death.
- Mitotic spindle function imaging.
- Kinetic analyses of cell death.
Main Results:
- DoHH2 cells exhibited mitotic arrest and apoptosis after 8 hours of taxol exposure.
- SU-DHL-4 cells, with mutant p53, showed delayed apoptosis (24 h) and abnormal cell-cycle progression despite equivalent mitotic spindle dysfunction.
- Cell death kinetics correlate with the rate of reaching a critical cell-cycle event window, irrespective of p53 status.
Conclusions:
- Low-dose taxol induces cell death primarily through mitotic stress triggering apoptosis, with outcomes potentially delayed in p53-mutant cells.
- The clinical efficacy of taxol may be independent of a tumor cell's intrinsic apoptosis capacity, even with mutations like p53.
- Findings support the design of combination therapies involving low-dose taxol and agents that disrupt mitotic progression.
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