Selective receptor modulators have been developed for steroid hormone receptors as a new class of mechanism-based drugs for treatment of hormone related diseases. We investigated an alternative mechanism-based strategy for treating various cancers with selective aryl hydrocarbon receptor modulators (SAhRMs), such as diindolylmetane/(DIM), 2,3,7,8-tetrachlorodibenzo-pdioxin/( TCDD), and 6-6-methyl-1,3,8-trichlorodibenzofuran/(MCDF) that exhibit antiproliferative activity in several cancer cell lines. MDA-MB-453 and BT-474 are estrogen receptor/(ER) negative breast cancer cell lines that express a functional aryl hydrocarbon receptor/(AhR) and treatment with SAhRMs significantly inhibited MDA-MB-453/BT-474 cell proliferation but did not significantly affect the percent distribution of cells in G0/G1/S/G2/M phases of cell cycle. TCDD and the SAhRMs had minimal effects on the expression of various cellular kinases. These data coupled with results obtained for other activated kinase pathways demonstrate that TCDD and SAhRMs uniquely inhibit growth of ER-negative MDA-MB 453/BT-474 breast cancer cells through kinase independent pathways. However, the SAhRMs induced HES-1, an antiproliferative transcription factor, in both cell lines and this might represent a possible mechanism for the growth inhibitory effects observed with these compounds. We proved that ring substituted DIMs exhibit androgenic/antiandrogenic activities in androgen receptor/(AR)-positive LNCaP/22RV1 prostate cancer cell lines resulting in antiproliferative activities. These antiproliferative activities were accompanied by antiandrogenic activity and structure-dependent down regulation of AR. The ring-substituted DIMs also induced both non-steroidal anti-inflamatory drug-induced gene-1/(NAG-1) and activating transcription factor 3/(ATF-3), two anti-proliferative/apoptotic genes which are responsible in part for the inhibitory effects of these compounds on the proliferation of prostate cancer cells.

Prostate cancer is the second leading cause of death from cancer in men in the United States. Most men will die of the advanced, metastatic form of the disease. Thus, treatment strategies targeting the metastatic form of the disease are especially needed. Emerging research on metastatic cancer highlights the importance of the microenvironment in cancer progression and metastasis, with an emphasis on deregulated developmental signaling in cancer progression. Research in model organisms has shown that developmental signaling pathways are regulated by various components of the extracellular matrix, including heparan sulfate proteoglycans. In the model system Drosophila, the heparan sulfate proteoglycan Trol is needed for Hhdependent proliferation in quiescent neural stem cells. In collaboration with others, I have shown that the human homolog of Trol, PERLECAN, regulates SONIC HEDGEHOG-dependent proliferation in advanced prostate cancer by two different mechanisms. This makes PERLECAN a potential drug target and biomarker for prostate cancer screening and treatment. My results also validate the discoveries made in Drosophila in the context of human disease. With this validation, I propose and describe the Drosophila Ejaculatory Bulb (EjB) as model for prostate cancer and prostate aging.

Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves.

Thesis (M. Psych. Clin.)--University of Queensland, 2002. / Includes bibliographical references.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

In the present study, the anti-tumor efficacy of α-TEA, a derivative of RRR-α-tocopherol, was investigated in LNCaP and PC-3-GFP human prostate cancer cells. Data show that α-TEA induced apoptosis in both cell lines in a time- and dose-dependent manner. Data show that α-TEA induces apoptosis through the activation of pro-apoptotic Fas signaling and inhibition of pro-survival Akt signaling pathways. The role of FADD and Daxx in α-TEA-induced apoptosis was determined. Data show that α-TEA promotes the association of FADD with Fas. FADD siRNA significantly reduced α-TEA-induced apoptosis in LNCaP cells. However, in PC-3-GFP cells, FADD siRNA caused apoptosis in the absence of α-TEA, and in the presence of FADD siRNA, α-TEA-induced apoptosis was significantly enhanced, indicating pro-survival activity of FADD in PC-3-GFP cells. Although α-TEA did not change the total protein levels of Daxx, it did promote the association of Daxx with Fas. α-TEA-induced apoptosis was significantly reduced by Daxx siRNA, and enhanced by overexpression of wild type Daxx, showing the pro-apoptotic role of Daxx in α-TEA-induced apoptosis. α-TEA inhibited phosphorylation of all three Akt isoforms; namely, Akt1, Akt2, and Akt3, thereby removed the phosphorylation inhibition on FOXO1 and FOXO1-mediated upregulation of FasL enhanced apoptosis through Fas signaling pathway. Studies have shown that selenium is of value in prostate cancer prevention. Here we document that methylseleninic acid (MSA) acts synergistically with α-TEA to induce apoptosis in LNCaP and PC-3-GFP human prostate cancer celld in culture. Western blot analyses indicate the involvement of caspases-8, -9, and -3, as well as Akt, in the synergistic effect of α-TEA and MSA. In a preclinical PC-3-GFP xenograft mouse model, α-TEA and MSC separately and together significantly reduced tumor burden and metastatic lesions in lungs and lymph nodes. However, synergism with the combination that in cell culture were not obtained in the animal study. α-TEA alone was as effective as, perhaps better than, the combination treatment in ruducing tumor burden and inhibiting metastases. Thus, data support α-TEA alone, rather than α-TEA plus selenium, as a treatment for human prostate cancer. / text

Anti-inflammatory specific cytokines and chemokines are elevated in many advanced tumors and correlate with poor prognosis. However, the differential expression of anti-inflammatory cytokines and chemokines in prostate cancer is not known. We investigated the hypotheses that androgen unresponsive DU145 and PC3 prostate cancer cells and androgen responsive LNCaP prostate cancer cells, differentially expressed selected anti-inflammatory and pro-inflammatory cytokines and chemokines and that, dendritic cells pulsed with prostate tumor antigens will induce mainly pro-inflammatory cytokines and chemokines in T cells using mouse models. Our results indicated that anti-inflammatory specific cytokines IL-1 0, IL-4, and anti-inflammatory specific chemokine CCL- 17 (TARC) and cognate receptor CCR4 are expressed in prostate cancer cell lines. Quantitative real-time PCR (qRT-PCR) revealed an almost five-fold increase in chemokine CCL17 and its cognate receptor CCR4 mRNA in androgen unresponsive DU145 and PC3 prostate cancer cell lines compared to androgen responsive prostate tumor LNCaP. Protein analysis indicated significantly increased secretion of anti-inflammatory cytokine IL- 10 by DU145 and PC3 compared to LNCaP. Furthermore, pro-inflammatory cytokine IFN-y and pro-inflammatory chemokine IP- 10 secretion were significantly less in these prostate cancer cells, when compared to immortalized normal prostate epithelial cells. Our in- vivo analysis revealed that T cells were activated by pulsed dendritic cells shown in the increase mRNA expression of pro-inflammatory cytokine IFN-y and pro-inflammatory chemokine IP- 10, and cognate receptor CXCR3. However, a predominant pro-inflammatory response was not observed as anti-inflammatory cytokines and chemokines were also seen. The production of anti-inflammatory cytokines and chemokines suggests a possible mechanism for prostate cancer to evade host immune responses by negatively modulating immune responses that are necessary for destroying cancers cells.. Cytokine and chemokine profiles could be used as potential prognostic markers for disease progression. Additionally, an effacious vaccine will depend on its ability to inhibit the recruitment of known distinct functional anti-inflammatory effector molecules, implicated in prostate cancer progression.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Pathology / Master / Master of Philosophy

No description available.