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- W1175683655 abstract "Proc Amer Assoc Cancer Res, Volume 45, 20045434 To develop strategies to enhance taxane-based therapies, we investigated the effects of cell cycle modulation on taxane efficacy. We and others have previously demonstrated that administration of paclitaxel followed by the cyclin-dependent kinase (cdk) inhibitor flavopiridol was synergistic. In that sequence, flavopiridol treatment resulted in an attenuation of paclitaxel-induced Cyclin B levels. We therefore hypothesized that an accelerated exit from taxane-induced M-phase arrest, via inhibition of the Cyclin B-Cdk1 complex, increases the anticancer activity of taxanes. Since flavopiridol has multiple targets beyond cdk inhibition that could account for the observed synergy, the selective cdk inhibitors roscovitine (ROS) and olomoucine (OLO) were employed in combination with paclitaxel to test this hypothesis. A549 cells were treated with 10nM paclitaxel for 24h and mitotic cells were collected and plated for colony formation assays. Cells were then treated with either ROS (1uM or 10uM) or OLO (50uM or 100uM) for 24h, or left without further treatment. Treatment with either agent resulted in significantly decreased colony formation compared to paclitaxel-only controls. ROS (10uM) decreased colony formation by over 40% (p<0.01) and OLO (100uM) by over 75% (p<0.001). A second set of experiments was conducted to determine whether mitotic cells are more sensitive than non-mitotic cells to the effects of flavopiridol in MCF-7 breast cancer cells. After paclitaxel treatment, mitotic and non-mitotic cells were separated and plated at equal densities. Half of the plates were subsequently treated with flavopiridol (200nM, 24h). In contrast to expectations, the mitotic fraction of paclitaxel-treated cells was over four times more viable than the non-mitotic fraction. However, flavopiridol treatment resulted in a 40% reduction in colony formation in the mitotic fraction (p<0.01) but had no significant effect on the non-mitotic fraction. Taken together, these data are supportive of our hypothesis that accelerated exit from taxane-induced M-phase arrest increases the anticancer activity of taxanes. It remains to be demonstrated whether Cdk1 inhibition results in a premature exit from M-phase, and if this exit is causative of the increased cell death. Further work will be conducted to determine the nature of the increased cytotoxicity (ie, apoptosis versus post-replicative cell death). (Supported by: ACS IRG 95-125-04 and UCD HSRA)" @default.
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- W1175683655 date "2004-04-01" @default.
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- W1175683655 title "Enhancing the anticancer activity of paclitaxel through cyclin-dependent kinase inhibition" @default.
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