Taxol, a naturally occurring antimitotic agent, has shown significant cell-killing activity against tumor cells by induction of apoptosis. However, the mechanism of taxol mediated cell death and its relationship with taxol's well-known effects on microtubules and mitotic arrest is not entirely clear. Recent studies in this laboratory demonstrated that taxol's cell-killing activity (but not mitotic arrest) is selectively inhibited if tumor cells were pretreated with glucocorticoids, suggesting that taxol-induced apoptosis might occur via a signaling pathway independent of mitotic arrest. On the other hand, since glucocorticoids (such as dexamethasone) are routinely used in the clinical application of taxol to prevent hypersensitivity reactions and other adverse effects, this finding also raises a clinically relevant question as to whether the pretreatment with glucocorticoids might interfere with taxol's antitumor efficacy. The objectives of this proposal are to elucidate the mechanism by which glucocorticoids inhibit taxol-induced apoptosis and determine its potential influence on taxol's therapeutic effect. Meanwhile, utilizing the unique inhibitory effect of glucocorticoids on taxol's action, this proposed research also tries to determine the molecular basis of taxol-induced apoptosis via a """"""""gene-directed"""""""" pathway. Therefore, this research application will pursue two major specific aims.
Aim 1 is to evaluate the potential inhibition of glucocorticoids on taxol and docetaxel's therapeutic effects in vivo through establishment of appropriate animal models.
This aim will confirm or negate the implication of glucocorticoid's effect on taxol or docetaxel's administration in vivo.
Aim 2 is to investigate the molecular mechanism underlying taxol-induced apoptosis and glucocorticoid-mediated drug resistance. Based on the latest progress, this study will focus on elucidating the possible role of the NF-kB/IkB-alpha signaling pathway in the regulation of apoptotic cell death induced by taxol and possibly other antimitotic agents in human solid tumor cells. The long-term goal of this research is to provide molecular insight into the mechanism and signal pathways that lead to taxol-induced cell death and glucocorticoid-mediated drug resistance. The information obtained from this proposed research may prove valuable for improving in the clinical application of this class of antineoplastic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092280-02
Application #
6624032
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Fu, Yali
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$254,540
Indirect Cost
Name
Medical University of South Carolina
Department
Pathology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Jiang, Donghai; Sui, Meihua; Zhong, Wangyan et al. (2013) Different administration strategies with paclitaxel induce distinct phenotypes of multidrug resistance in breast cancer cells. Cancer Lett 335:404-11
Sui, Meihua; Zhang, Hongfang; Di, Xiaoyun et al. (2012) G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy. Radiother Oncol 104:243-8
Xiong, Xiaoxiong; Sui, Meihua; Fan, Weimin et al. (2007) Cell cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy. Cancer Biol Ther 6:1067-73
Sui, Meihua; Huang, Yi; Park, Ben Ho et al. (2007) Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death. Cancer Res 67:5337-44
Sui, Meihua; Chen, Feng; Chen, Zhi et al. (2006) Glucocorticoids interfere with therapeutic efficacy of paclitaxel against human breast and ovarian xenograft tumors. Int J Cancer 119:712-7
Sui, Meihua; Xiong, Xiaoxiong; Kraft, Andrew S et al. (2006) Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis. Cancer Biol Ther 5:1015-21
Sui, Meihua; Fan, Weimin (2005) Combination of gamma-radiation antagonizes the cytotoxic effects of vincristine and vinblastine on both mitotic arrest and apoptosis. Int J Radiat Oncol Biol Phys 61:1151-8
Zhu, Xueming; Sui, Meihua; Fan, Weimin (2005) In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel. Anticancer Res 25:1953-62
Sui, Meihua; Dziadyk, Jennifer M; Zhu, Xueming et al. (2004) Cell cycle-dependent antagonistic interactions between paclitaxel and gamma-radiation in combination therapy. Clin Cancer Res 10:4848-57
Fan, Weimin; Sui, Meihua; Huang, Yi (2004) Glucocorticoids selectively inhibit paclitaxel-induced apoptosis: mechanisms and its clinical impact. Curr Med Chem 11:403-11

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