Loss of apoptotic control in prostate growth disorders involves the altered expression/activation of downstream intracellular effectors of apoptosis signaling pathways. Re-instating functional apoptotic mechanisms, by targeting specific components in this pathway, are of high significance in the regulation of prostate growth. Recent studies documented the ability for quinazoline-based a1-adrenoceptor antagonists, doxazosin and terazosin, to induce apoptosis in human prostate smooth muscle, benign and malignant epithelial cells, via an a1-adrenoceptor independent mechanism and suppress tissue vascularity. Our hypothesis is that quinazoline-based a1-adrenoceptor antagonists suppress prostate growth by inducing apoptosis (via induction of intracellular signaling effectors) and inhibit angiogenesis by promoting anoikis (via interference with extracellular matrix attachments). To test this hypothesis, the following aims are proposed:
In Specific Aim 1 we will use DNA microarray analysis and proteomic analysis to identify intracellular signaling effectors of apoptosis induced by quinazoline-based a1-adrenoceptor antagonists in prostate benign and malignant cells.
Specific Aim 2 will identify the extracellular matrix components involved in quinazoline-induced anoikis in prostate epithelial and endothelial cells with focus on Fas-Fasligand-caspase-8 activation mechanism and integrin effectors.
Specific Aim 3 will establish that the quinazolines, doxazosin and terazosin, suppress prostate vasculature and inhibit tissue angiogenesis in patients after a1 blockade treatment. Immunohistochemical analysis will be performed on tissue specimens from BPH patients treated with a1 blockade (for obstructive symptoms) using antibodies against Factor VIII (microcrossed density), vascular endothelial growth factor (VEGF), and focal ashesion kinase (FAK). The goal of the proposed studies is to determine the early response genes at the intracellular (TGF-beta) and extracellular matrix (integrins) environment underlying the quinazoline-mediated apoptosis, targeted by this pharmacologic intervention in benign and malignant prostate growth. Potential results will establish the apoptotic/anoikis effect by the quinazolines as a significant phenomenon with clinical relevance in development and progression of benign prostatic hyperplasia (BPH) prostate cancer.
|Bilbro, Johnathan; Mart, Matthew; Kyprianou, Natasha (2013) Therapeutic value of quinazoline-based compounds in prostate cancer. Anticancer Res 33:4695-700|
|Hensley, Patrick J; Kyprianou, Natasha (2012) Modeling prostate cancer in mice: limitations and opportunities. J Androl 33:133-44|
|Desiniotis, Andreas; Kyprianou, Natasha (2011) Advances in the design and synthesis of prazosin derivatives over the last ten years. Expert Opin Ther Targets 15:1405-18|
|Sakamoto, Shinichi; Schwarze, Steven; Kyprianou, Natasha (2011) Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma. Eur Urol 59:734-44|
|Desiniotis, Andreas; Kyprianou, Natasha (2011) Significance of talin in cancer progression and metastasis. Int Rev Cell Mol Biol 289:117-47|
|Matuszak, Emily A; Kyprianou, Natasha (2011) Androgen regulation of epithelial-mesenchymal transition in prostate tumorigenesis. Expert Rev Endocrinol Metab 6:469-482|
|Sakamoto, Shinichi; McCann, Richard O; Dhir, Rajiv et al. (2010) Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance. Cancer Res 70:1885-95|
|Zhu, Meng-Lei; Horbinski, Craig M; Garzotto, Mark et al. (2010) Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res 70:7992-8002|
|Sakamoto, Shinichi; Kyprianou, Natasha (2010) Targeting anoikis resistance in prostate cancer metastasis. Mol Aspects Med 31:205-14|
|Zhu, Meng-Lei; Kyprianou, Natasha (2010) Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J 24:769-77|
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