| Quinazoline-based alpha1-adrenoceptor antagonists such as doxazosin and terazosin induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent pathway. The apoptotic effect of the quinazoline-based doxazosin occurs via the activation of latent apoptotic machinery involving TGF-beta1 signaling and IkappaBalpha. My dissertation focused on the mechanism of doxazosin-mediated apoptosis and developing novel quinazoline-based compounds towards the effective elimination of prostate cancer. I provide evidence that doxazosin induces apoptosis via the death receptor-mediated pathway. Furthermore, by using a structure-function analysis approach to structurally modify doxazosin's chemical nucleus I have developed a novel class of apoptosis-inducing agents as well as a class of angiogenesis-targeting agents.;In this study the molecular events initiating this apoptotic effect were investigated. Quantitative microarray analysis demonstrated that doxazosin initiates transient changes in the expression of several apoptosis regulators. I also show significant changes in the expression pattern of key signaling components of the extracellular matrix such as integrins alpha2, beta 8, alphaV and beta1. Doxazosin was shown to cause caspase-8 mediated apoptosis via DISC formation. These results demonstrate that doxazosin exerts its apoptotic effects via a death-receptor mediated mechanism with an integrin contribution towards cell survival outcomes.;The study subsequently pursued was a drug-discovery approach, and a structure-function analysis revealed structural modification of doxazosin's chemical nucleus allows for the development of a novel class of apoptosis-inducing agents as well as a class of angiogenesis-targeting agents. The lead compound, DZ-50, is effective at reducing cell viability via a non-apoptotic mechanism. Treatment with DZ-50 prevented in vitro tube formation and in vivo chorioallantoic membrane vessel development. Moreover, there was a significant reduction in the efficiency of tumor cells to attach and migrate through monolayers of endothelial cells in the presence of DZ-50. In vivo tumorigenicty studies using human prostate cancer xenografts in nude mice demonstrated the ability of relatively low doses of DZ-50 to significantly suppress of prostate tumor growth. Furthermore, DZ-50 administration results in a reduced appearance of lung metastasis in an in vivo spontaneous metastasis assay. These findings suggest that this new class of quinazoline-based compounds has considerable promise as novel anti-tumorigenic drugs for the treatment of advanced prostate cancer.;Keywords. Prostate Cancer, Doxazosin, Apoptosis, DISC, Angiogenesis. |
