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Glucocorticoids Selectively Inhibit Paclitaxel-Induced Apoptosis: Mechanisms and Its Clinical Impact

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Abstract:

Paclitaxel (Taxol™), a naturally occurring antimitotic agent, has shown significant cell-killing activity against tumor cells through induction of apoptosis. The mechanism by which paclitaxel induces cell death is not entirely clear. Recent studies in our laboratory discovered that glucocorticoids selectively inhibited paclitaxel-induced apoptosis without affecting the ability of paclitaxel to induce microtubule bundling and mitotic arrest. This finding implies that apoptotic cell death induced by paclitaxel may occur via a pathway independent of mitotic arrest. Through analyses of a number of apoptosis-associated genes or regulatory proteins, we found that glucocorticoids and paclitaxel possess opposite regulatory role in the NF- κB / IκBα signaling pathway. Further studies indicate that paclitaxel activates IκB Kinase (IKK), which in turn causes degradation of IκBα and activation of NF-κB, whereas glucocorticoids antagonize paclitaxel-mediated NF-κB activation through induction of IκBα synthesis. These results suggest that the NF-κB / IκBα signaling pathway might play a critical role in the mediation or regulation of paclitaxel-induced cell death. On the other hand, since glucocorticoids (such as dexamethasone) are routinely used in the clinical application of paclitaxel to prevent hypersensitivity reactions and other adverse effects, the inhibitory action of glucocorticoids on paclitaxel-induced apoptosis also raises a clinically relevant question as to whether the pretreatment with glucocorticoids might interfere with the therapeutic efficacy of paclitaxel.

Keywords: apoptosis; glucocorticoids; kinase; microtubules; mitotic arrest; paclitaxel

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867043455990

Affiliations: Department of Pathology and Laboratory, Medical University of South Carolina, 165 Ashley Avenue, Charleston, SC 29425, USA.

Publication date: February 1, 2004

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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