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Part 1: Troglitazone analogues as cyclin D1 ablative agents: the potential drugs for breast cancer therapy Part 2: Vitamin E and its analogues induce apoptosis in prostate cancer cells in part through inhibition of Bcl-2/Bcl-xL functions

by Huang, Jui-Wen

Abstract (Summary)
Part 1: Cyclin D1 overexpression has been implicated in oncogene-induced mammary tumorigenesis as it is detected in over 50% of primary breast carcinomas. It has been reported that troglitazone (TG), a peroxisome proliferator-activated receptor gamma(PPAR gamma) agonist, can induce degradation of cyclin D1 as part of its mechanism for causing cell cycle arrest and growth inhibition in breast cancer cells. In this study, we obtained evidence that the ability of high doses of TG to repress cyclin D1 is independent of PPAR gamma activation. In addition, TG- and Delta2-TG-induced cyclin D1 repression is mediated via proteasome-facilitated proteolysis as it can be inhibited by multiple proteasome inhibitors and is preceded by increased ubiquitination. The dissociation of these two pharmacological activities provides a molecular basis to use Delta2-TG as a scaffold to develop a novel class of cyclin D1-ablative agents. Accordingly, a small library of Delta2-TG derivatives has been synthesized. Among derivatives in this library, Delta2-TG-28 represents a structurally optimized agent with potency an-order-of-magnitude higher than that of Delta2-TG in cyclin D1 repression and MCF-7 cell growth inhibition. Part 2: Vitamin E and its analogues have been shown to be proapoptotic agents in cancer cells, but the precise mechanism of their antineoplastic activity is not fully elucidated. To investigate the mechanism and the relationships between the structures and apoptosis-inducing activities of vitamin E and alpha-TOS, a series of vitamin E analogues were synthesized. Among these analogues, compound VEA-7 exhibits the most potent proapoptotic activity. Fluorescence polarization analysis and immunoprecipitation data confirmed that alpha-TOS and most apoptosis-inducing vitamin E analogues inhibit the proliferation of PC-3 and LNCaP prostate cancer cells in part by repressing the heterodimerization of Bcl-2/Bcl-XL and Bax. VEA-7 also displays stronger Bcl-XL binding affinity. In addition, alpha-TOS and these vitamin E analogues selectively induce apoptosis in malignant prostate cancer cells but not in normal prostate epithelial cells. The synthetic vitamin E analogue, VEA-7, represents a novel apoptogenic agent that may have clinical value in chemotherapeutic strategies for prostate cancer in the future.
Bibliographical Information:

Advisor:

School:The Ohio State University

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:cyclin d1 ppar gamma troglitazone breast cnacer vitamine e apoptosis bcl 2 inhibitor prostate cancer

ISBN:

Date of Publication:01/01/2005

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