Pacientes submetidos por longos períodos à diálise peritoneal (DP) podem evoluir com fibrose e redução da capacidade de ultrafiltração da membrana peritoneal (MP). Essas alterações da MP são desencadeadas pela exposição prolongada às soluções de diálise peritoneal, peritonites de repetição e irritantes químicos que induzem inflamação, neoangiogênese e fibrose da MP. A ativação da via Transforming Growth Factor (TGF-beta)/Smad é um fundamental mecanismo mediador da fibrogênese peritoneal. Sendo assim, drogas que inibam a via TGF-beta/Smad são de especial interesse no tratamento da FP. O ácido valpróico (VPA) é um inibidor das histona desacetilases (iHDAC), enzimas que regulam a conformação da cromatina e a expressão gênica, com atividade anti-inflamatória e antifibrótica. O presente estudo tem como objetivo principal avaliar o efeito do VPA em um modelo experimental de fibrose peritoneal em ratos. Vinte e quatro ratos Wistar machos (peso inicial de 280 - 320g) foram dividos em 3 grupos experimentais: CONTROLE (n=8), animais normais que receberam injeções de salina intraperitoneal (IP); FP (n=8), animais que recereberam injeções IP de gluconato de clorexidina (GC) diariamente por 15 dias para indução de fibrose peritoneal; FP+VPA (n=8), animais com FP e tratados com VPA. O ácido valpróico (300mg/kg) foi administrado por gavage diariamente por 15 dias, simultaneamente à indução de fibrose peritoneal. Ao fim dos experimentos, amostras do tecido peritoneal foram coletadas para realização de histologia, imunho-histoquímica (IH), imunofluorescência (IF) e biologia molecular. A análise da MP dos animais do grupo FP revelou um espessamento significativo da camada submesotelial devido ao acúmulo de matriz extracelular e infiltrado inflamatório. O tratamento com VPA foi capaz de prevenir significativamente o espessamento da MP, mantendo a espessura do peritôneo do grupo FP+VPA similar a do grupo CONTROLE. Com relação à função peritoneal, a administração de VPA evitou a queda da ultrafiltração e aumento do transporte peritoneal de glicose induzidos pelo GC. Além disso, o VPA impediu o aumento da expressão de miofibroblastos e de fatores associados à fibrose (TGF-beta, FSP-1 e fibronectina) induzidos pelo GC. Interessantemente, o VPA reduziu de maneira significativa a expressão da Smad3, mediador intracelular crítico da sinalização TGF-beta/Smad, em relação ao grupo FP. Por outro lado, os animais tratados com VPA apresentaram um aumento da expressão peritoneal de fatores antifibróticos como a BMP-7 e Smad7, proteínas que contrarregulam as ações do TGF-beta. Além de atenuar a fibrose peritoneal, o VPA apresentou efeitos anti-inflamatório e antiangiogênico, demonstrado pela menor expressão de citocinas pró-inflamatórias, fatores quimiotáticos para macrófagos (MCP-1) e VEGF no grupo FP+VPA quando comparado ao grupo FP. Em resumo, o VPA foi capaz de bloquear o espessamento por fibrose da MP e preservar a sua função, além de proteger o peritônio contra a neoangiogênese e inflamação. Além disso, o VPA induziu um aumento da expressão de fatores antifibróticos na MP. Os resultados apresentados neste trabalho chamam a atenção para mecanismos envolvidos nas modificações da MP induzidas pela DP ainda pouco explorados e que podem constiuir potenciais alvos na prevenção do desenvolvimento da fibrose peritoneal associada à DP / Long term peritoneal dialysis (PF) can induce peritoneal fibrosis and loss of ultrafiltration capacity of peritoneal membrane (PM). These peritoneal changes are due to prolonged exposure to peritoneal dialysis solutions, chemical irritants and acute peritonitis episodes that induce inflammation, neoangiogenesis and PM fibrosis. The Transforming Growth Factor (TGF-?) is the main mediator involved in the development of peritoneal fibrosis. Thus, drugs that inhibit the TGF-?/Smad pathway or inflammation are of particular interest in the treatment of PF. Valproic acid (VPA) is an histone deacetylase (HDAC) inhibitor. HDACs are enzymes that regulate chromatin conformation and gene expression. Recent studies have described HDACi as promising drugs in the treatment of inflammatory and fibrotic diseases. The main aim of this study was to evaluate the effect of VPA in an experimental model of peritoneal fibrosis in rats. Twenty four Wistar rats (initial weight of 280-320g) were divided into three experimental groups: CONTROL (n = 8), normal animals that received only saline ip; FP (n = 8), peritoneal fibrosis was induced by daily Gluconate Clorhexedine (GC) intraperitoneal (IP) injections for 15 days; FP+VPA (n = 8), animals with peritoneal fibrosis and treated with VPA. Daily valproic acid (300mg/kg) doses were administered by gavage simultaneously with the induction of peritoneal fibrosis in the FP+VPA group. At the end of experiments, the animals were submitted to euthanasia and samples of peritoneal tissue were collected for histology, immunocytochemistry, immunofluorescence, and molecular biology. Also, a functional peritoneal test was performed. The FP group showed a significant thickening of PM due to the accumulation of extracellular matrix and inflammatory cellular infiltration. VPA treatment was able to significantly prevent PM thickening, maintaining the peritoneal thickness of the VPA group similar to that of the CONTROL group. The VPA administration also preserved peritoneal function in the FP+VPA group, avoiding the reduction of ultrafiltration and increasing of peritoneal glucose transport induced by GC. According to the histological changes mentioned above, the VPA hampered the upregulation of the pro-fibrotic genes (TGF-beta, FSP-1, and fibronectin) and increase in the myofibroblasts expression induced by GC injections. Interestingly, the peritoneal expression of phosphorylated Smad3 detected by immunohistochemistry and Smad3 mRNA was significantly higher in the FP group. However, this effect was attenuated by VPA treatment. On the other hand, VPA was able to induce an increase in the expression of the antifibrotic factors, such as BMP-7 and Smad7, in the peritoneal membrane. Besides its antifibrotic activity, VPA also showed anti-inflammatory and anti-angiogenic effects. Animals of the FP+VPA group showed a significant reduction of the PM expression of pro-inflmmatory cytokines, macrophage chemoattractants and, VEGF expression when compared with FP group. In conclusion, we have shown that VPA inhibits the progression of peritoneal fibrosis in a CG-induced peritoneal fibrosis model in rats. VPA inhibited different and important mechanisms involved in peritoneal membrane modifications induced by PD, as activation of TGF-beta/Smad pathway, inflammation, and angiogenesis. Notably, VPA induced the expression of antifibrotic factors. Our results are very interesting and shed lights on a new perspective for the treatment of peritoneal fibrosis. However, this is an exploratory study and future studies are needed before to translate this experimental finding into clinical application

Nuclear hormone receptors (NHR) constitute a superfamily of ligand inducible transcriptional activators that enable an organism to regulate development and homeostasis through switching on or off target genes in response to stimuli reflecting changes in environment as well as endocrine. NHRs include classical steroid hormone receptors (GR, AR, ER and MR) and retinoid, thyroid hormone receptors. One long-term goal of our lab is to understand the molecular mechanisms through which the transcriptional activity of NHRs is regulated. Extensive studies in the past few years have revealed that in addition to the dependence on ligand availability, the transcriptional activity of NHRs is also regulated by two types of proteins: co activators and corepressors. In the absence of ligand, many NHRs, including TR and RAR can actively repress target gene transcription with the help of corepressors, proteins that physically interact with both NHRs and histone deacetylases (HDACs). Functional interactions between NHRs and corepressors therefore lead to tightly compact and transcriptionally non-permissive chromatin structures after the removal of obstructive acetyl groups from histone tails by HDACs. On the other hand, ligand binding stabilizes NHRs in a conformation that favors interaction with proteins other than corepressors; many of these proteins are able to potentiate the transcriptional activity of NHRs through various mechanisms, such as histone acetylation, chromatin remodeling and recruitment of basal transcription machinery and are collectively termed coactivators. Two highly related corepressors, SMRT (silencing mediator of retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor), have been cloned. This research in corepressor SMRT started by a systematic study of its subcellular localization. We found that SMRT predominantly forms a specific nuclear punctuate structure that does not appear to overlap with any other well-known subnuclear domains/speckles. Although our searching for specific sequence signals that may determine the specific speckle localization of SMRT did not yield conclusive results, we discovered the colocalization of unliganded RAR and certain HDACs, including HDAC1, 3,4 and 5, in the SMRT nuclear speckles. Moreover, SMRT is likely to be the organizer of such speckles since it appears to be able to recruit other proteins into these speckles. The presence of HDAC1 in the SMRT speckles suggests a direct association between these two proteins, which has not been detected by previous biochemical analyses. Interestingly, HDAC1 point mutants that are completely defective in deacetylase activity failed to locate to SMRT nuclear speckles, while another partially active mutant maintained the colocalization. These discoveries may indicate SMRT nuclear speckles as novel nuclear domains involved in transcriptional repression. More physiologically relevant support for this hypothesis arises from study of HDAC4 and 5. HDAC4 and 5 are potent inhibitors of transcriptional activator MEF2C. Nuclear presence of HDAC4/5 can block the activation of MEF2C, which is required during muscle differentiation. Normally, HDAC4 is predominantly located in cytoplasm. However, we found that in the presence of SMRT overexpression, HDAC4 was found mostly in SMRT nuclear speckles. This accumulation enhanced HDAC4 mediated inhibition on MEF2C transcriptional activity in a transient transfection assay. SMRT overexpression also resulted in accumulation of HDAC5 in the SMRT nuclear speckles compared to the nuclear diffuse distribution in the absence of SMRT. Again, this accumulation of HDAC5 in nuclear speckles correlated with enhanced inhibition of MEF2C. Taken together, our study suggested that instead of being merely a corepressor for NHRs, SMRT might function as an organizer of a nuclear repression domain, which may be involved in a broad array of cellular processes. In contrast to the limited number of corepressors, numerous co activators have been identified; the SRC (or p160) family is relatively well studied. This family includes three highly related members, SRC-1, TIF2/GRIP1, RAC3/AIB1/ACTR/p/CIP. Similar domain structures are shared among these factors, with the most highly conserved region, the bHLH-PAS domain found within the N terminal ~400 amino acid residues. This study of RAC3 aims to identify the function of the highly conserved N terminal bHLH-PAS domain by isolating interacting proteins through yeast two-hybrid screening. One candidate gene isolated encodes the C terminal fragment of the human homologue of the yeast protein MMS19. Functional studies of this small fragment revealed that it specifically interacted with human estrogen receptors (ERs) and inhibited ligand induced transcriptional activity of ERs in the transient transfection assay. Then we cloned the full-length human MMS19 cDNA and characterized the hMMS19 as a weak coactivator for estrogen receptors in the transient transfection assay. Furthermore, when tested on separate AF-1 or AF-2 of ERs, hMMS19 specifically enhanced AF-1 but had no effect on AF-2. These results identified hMMS19 as a specific coactivator for ER AF-1.

Tang Angie. / Thesis submitted in: November 2005. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 151-172). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.iii / Abstract in Chinese --- p.vi / Table of Contents --- p.vii / List of Publications --- p.xi / Awards --- p.xii / List of Abbreviations --- p.xiii / List of Tables --- p.xv / List of Figures --- p.xvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter Chapter 2 --- Literature Review --- p.3 / Chapter 2.1 --- Gastric cancer-overview --- p.3 / Chapter 2.1.1 --- Epidemology --- p.3 / Chapter 2.1.2 --- Pathology --- p.3 / Chapter 2.1.3 --- Etiologies and Risk Factors --- p.4 / Chapter I. --- Environmental factors --- p.4 / Chapter a. --- Helicobacter pylori infections --- p.4 / Chapter b. --- Epstein-Barr virus (EBV) --- p.6 / Chapter c. --- Dietary factors --- p.6 / Chapter d. --- Smoking --- p.6 / Chapter II. --- Genetic Factors --- p.7 / Chapter a. --- Hereditary Gastric Cancer --- p.7 / Chapter b. --- Genetic polymorphism --- p.8 / Chapter III. --- Cyclooxygenases (COX) enzymes --- p.10 / Chapter IV. --- Molecular carcinogenesis --- p.11 / Chapter a. --- Activation of proto-oncogenes --- p.11 / Chapter b. --- Candidate tumor suppressor genes --- p.12 / Chapter 1. --- Gene mutation and deletion --- p.12 / Chapter 2. --- Epigenetic Silencing --- p.13 / Chapter 2.2 --- Epigenetics --- p.14 / Chapter 2.2.1 --- DNA methylation --- p.15 / Chapter 2.2.2 --- Histone modification --- p.28 / Chapter I. --- Histone acetylation and deacetylation --- p.32 / Chapter II. --- Histone methylation --- p.32 / Chapter III. --- Histone phosphorylation --- p.34 / Chapter IV. --- Histone ubiquitylation --- p.34 / Chapter 2.3 --- "HAT, HDAC and HDAC inhibitors" --- p.36 / Chapter 2.3.1 --- HAT --- p.38 / Chapter 2.3.2 --- HDAC --- p.39 / Chapter (a) --- Class I --- p.40 / Chapter (b) --- Class II --- p.41 / Chapter (c) --- Class III --- p.42 / Chapter (d) --- Mammalian HDAC and their mechanism of deacetylation --- p.44 / Chapter 2.3.3 --- HDAC inhibitors --- p.45 / Chapter I. --- Class I/II natural inhibitors --- p.47 / Chapter II. --- Class I/II synthetic inhibitors --- p.48 / Chapter III. --- Sirtuins inhibitors --- p.49 / Chapter IV. --- Activity of HDAC inhibitors in vitro --- p.50 / Chapter a. --- Effect in the gene expression --- p.50 / Chapter b. --- Non-transcriptional effects --- p.55 / Chapter c. --- Activity of HDAC inhibitors with other agents --- p.57 / Chapter d. --- Effects in xenograft tumor models --- p.57 / Chapter V. --- Clinical trials of HDAC inhibitors --- p.59 / Chapter Chapter 3 --- Aims of the study --- p.63 / Chapter Chapter 4 --- Materials and Methods --- p.64 / Chapter 4.1 --- Cell culture --- p.64 / Chapter 4.2 --- Drug treatment --- p.64 / Chapter 4.2.1 --- Suberoylanilide Hydroxamic Acid treatment --- p.64 / Chapter 4.2.2 --- Trichostatin A treatment --- p.65 / Chapter 4.3 --- Cell proliferation assay --- p.66 / Chapter 4.4 --- Apoptotic assay --- p.67 / Chapter 4.5 --- Flow cytometry --- p.67 / Chapter 4.5.1 --- Cell preparation --- p.67 / Chapter 4.5.2 --- Propidium Iodide staining --- p.68 / Chapter 4.5.3 --- Annexin V-FITC staining --- p.68 / Chapter 4.5.4 --- Flow cytometer analysis --- p.69 / Chapter 4.6 --- Total RNA extraction --- p.70 / Chapter 4.7 --- DNA extraction --- p.71 / Chapter 4.8 --- Protein extraction --- p.72 / Chapter 4.9 --- Western blottng --- p.72 / Chapter 4.10 --- Microarray analysis --- p.74 / Chapter 4.10.1 --- Sample preparation for microarray --- p.74 / Chapter 4.10.2 --- Hybridization --- p.75 / Chapter 4.10.3 --- Scanning and data processing --- p.75 / Chapter 4.10.4 --- Data analysis --- p.76 / Chapter 4.11 --- Primer design --- p.77 / Chapter 4.12 --- RT-PCR --- p.77 / Chapter 4.12.1 --- Reverse transcription --- p.77 / Chapter 4.12.2 --- Quantitative RT-PCR --- p.78 / Chapter 4.13 --- Methlyation study --- p.79 / Chapter 4.13.1 --- Demethylation by 5-aza-2'deoxycytidine --- p.79 / Chapter 4.13.2 --- Bisulfite modification --- p.79 / Chapter 4.13.3 --- Methylation-specific PCR (MSP) --- p.79 / Chapter Chapter 5 --- Results --- p.81 / Chapter 5.1 --- Morphological changes in AGS cells --- p.81 / Chapter 5.2 --- Anti-cancer effects of HDAC inhibitors --- p.81 / Chapter 5.2.1 --- Effect of HDAC inhibitors on cell growth --- p.81 / Chapter a. --- SAHA inhibits cell proliferation --- p.82 / Chapter b. --- TSA inhibits cell proliferation --- p.82 / Chapter 5.2.2 --- Cell cycle analysis --- p.87 / Chapter a. --- Effect of SAHA on cell cycle --- p.87 / Chapter b. --- Effect of TSA on cell cycle --- p.88 / Chapter 5.2.3 --- Induction of apoptosis on AGS cells --- p.92 / Chapter a. --- SAHA induces apoptotic cell death --- p.92 / Chapter b. --- TSA induces apoptotic cell death --- p.94 / Chapter 5.3 --- Induction of histone expression on AGS cells --- p.102 / Chapter 5.3.1 --- HDAC inhibitors induced acetylation of histone H3 --- p.102 / Chapter 5.3.2 --- HDAC inhibitors induced acetylation of histone H4 --- p.103 / Chapter 5.4 --- SAHA- and TSA-induced gene expression profiles --- p.106 / Chapter 5.5 --- Verification of gene expression by quantitative RT-PCR --- p.108 / Chapter 5.6 --- Methylation study --- p.113 / Chapter Chapter 6 --- Discussion --- p.116 / Chapter 6.1 --- Improved treatment strategy is needed for gastric cancer. --- p.116 / Chapter 6.2 --- HDAC inhibitors as potential anti-cancer agents --- p.117 / Chapter 6.3 --- Potential anti-cancer effect of TSA and SAHA on AGS cells --- p.120 / Chapter I. --- Morphological changes of AGS gastric cancer cells --- p.120 / Chapter II. --- Inhibition of cell proliferation --- p.120 / Chapter III. --- Induction of cell cycle arrest --- p.121 / Chapter IV. --- Induction of apoptosis --- p.122 / Chapter 6.4 --- Expression of acetylated histones upon treatment with TSA and SAHA --- p.124 / Chapter 6.5 --- Identify potential target genes upon treatment with TSA and SAHA --- p.125 / Chapter 6.5.1 --- Candidate genes involved in cell cycle --- p.126 / Chapter a. --- P21WAF1 --- p.126 / Chapter b. --- p27kip1. --- p.128 / Chapter c. --- Cyclin E & Cyclin A --- p.128 / Chapter d. --- Signal-induced proliferation-associated gene 1 (SIPA1) .… --- p.129 / Chapter 6.5.2 --- Candidate genes involved in apoptosis and anti-proliferation --- p.130 / Chapter a. --- BCL2-interacting killer (apoptosis-inducing) (BIK) (Pro-apoptotic gene) --- p.131 / Chapter b. --- Thioredoxin interacting protein (TXNIP) (Proapoptotic gene) / Chapter c. --- Cell death-inducing DFFA-like effector b (CIDEB) (apoptosis induction) --- p.132 / Chapter d. --- B-cell translocation gene 1 (BTG1) - (anti-proliferation) --- p.133 / Chapter e. --- Quiescin 6 (QSCN6) (anti-proliferation) --- p.133 / Chapter f. --- "Cysteine-rich, angiogenic inducer, 61 (CYR61) (anti-proliferative)" --- p.134 / Chapter g. --- Metallothionein 2A (MT2A) (apoptosis induction and anti-proliferative) --- p.134 / Chapter 6.5.3 --- Other genes reported to be up-regulated with HDAC inhibitors treatment --- p.135 / Chapter a. --- Glia maturation factor-gamma (GMFG) --- p.135 / Chapter b. --- v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) / Chapter c. --- Interleukin 8 (IL-8) --- p.136 / Chapter d. --- Insulin-like growth factor binding protein- 2 (IGFBP2) --- p.137 / Chapter e. --- Integrin alpha chain 7 (ITGA7) --- p.138 / Chapter 6.5.4 --- Selected highly up-regulated genes with HDAC inhibitors treatment --- p.139 / Chapter a. --- Aldo-keto reductase family 1，member C3 (AKR1C3) --- p.139 / Chapter b. --- GPI-anchored metastasis-associated protein homolog (C4.4A) --- p.139 / Chapter c. --- "Serine (or cysteine) proteinase inhibitor，clade I (neuroserpin), member 1 (SERPINI1)" --- p.140 / Chapter d. --- "Serine (or cysteine) proteinase inhibitor，clade E (nexin, plasminogen activator inhibitor type 1), member 1 (SERPINE1)" --- p.140 / Chapter e. --- Adrenomedullin (ADM) --- p.141 / Chapter f. --- Dehydrogenase/reductase (SDR family) member 2 (HEP27) --- p.142 / Chapter g. --- Cholecystokinin (CCK) --- p.142 / Chapter h. --- Silver homolog (mouse) (SILV) --- p.143 / Chapter 6.6 --- Genes regulated by gene promoter hypermethylation in AGS cells --- p.143 / Chapter Chapter 7 --- Conclusion --- p.147 / Chapter Chapter 8 --- Further Studies --- p.150 / References --- p.151 / Appendix I --- p.151 / Appendix II --- p.III / Appendix III --- p.IV / Appendix IV --- p.VI

The major evolutionary transition from single-celled to multicellular life is believed to have occurred independently of the main metazoan lineages in the cellular slime moulds, of which Dictyostelium discoideum is the best-studied species. Unusually, in this case multicellular development is a facultative trait and part of an asexual life cycle. It is triggered by starvation and involves aggregation of hitherto independent and possibly unrelated free-living cells. The consequences of multicellularity in D.discoideum are strongly influenced by the environment and meaningful external perturbations are easily carried out. This makes the organism ideally suited to a study of epigenetic factors that regulate development. In an attempt to understand how conserved epigenetic pathways are integrated within the developmental framework, two likely players were chosen for investigation - heat shock protein 90 (Hsp90) and histone deacetylases (HDACs). Hsp90 has been implicated in diverse biological processes such as protein folding, cell cycle control, signal transduction, and morphological evolution. The role of Hsp90 in D.discoideum life cycle was studied using a specific inhibitor, geldanamycin. Inhibition of Hsp90 function in D.discoideum caused a delay in aggregation and an arrest of development at the ‘mound’ stage. A reduction in Hsp90activity in starving cells of D.discoideum resulted in the generation of a range of phenotypes. The study suggests that Hsp90 is required for a specific developmental transition of the social amoeba and is important in generating a reliable outcome of the developmental process. Histone acetylation regulates gene expression and leads to the establishment and maintenance of cellular phenotypes during development of plants and animals. To study the roles of HDACs in D.discoideum, biochemical, pharmacological and genetic approaches were employed. The inhibition of HDAC activity by trichostatin A resulted in histone hyperacetylation and a delay in cell aggregation and differentiation. Cyclic AMP oscillations were normal in starved amoebae treated with trichostatin A but the expression of a subset of cAMP-regulated genes was delayed. Bioinformatic analysis indicated that there are four genes encoding putative HDACs in D.discoideum. One of these four genes, hdaB, was found to be dispensable for growth and development under laboratory conditions; but formed spores with lower efficiency than the wild type in chimeras. The work shows that HDAC activity is important for regulating two aspects of multicellular development: (a) heterochrony, namely the relative timing of developmental events, and (b) modulating the behaviour of single cells in a manner that is sensitive to their social environment.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references. Also available online.

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The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), is a key calcium (Ca++) regulatory hormone. It is also associated with functions unrelated to Ca++ homeostasis. Here, special attention is paid towards the anticancer properties of 1,25D. 1,25D strongly inhibits the growth of well-differentiated head and neck squamous cell carcinoma (HNSCC) derived cell lines. However, advanced, less differentiated, HNSCC cell lines (e.g. SCC4) are partially resistant to 1,25D. Resistance to nuclear receptor (NR) agonists is a common event that occurs in other NR-related treatments. For example, some leukemias develop resistance to the usually effective retinoic acid (RA) treatment. However, treating RA-resistant cells with HDAC inhibitors (HDACi) sensitizes them to RA. Thus, this study aims to investigate how treatment with TSA, an HDACi, would affect the response of SCC4 cell lines to 1,25D. We found that TSA had a variety of effects on 1,25D-regulated gene expression. Combined treatment with 1,25D and TSA increased the expression of cell-cycle regulating proteins, but also enhanced the downregulation of key target genes. Given the potential of the 1,25D/HDACi combination in combating cancers, two chimeric compounds, each containing parts of 1,25D and an HDACi, were synthesized in collaboration with Dr. James Gleason (Dept. of Chemistry, McGill). These 1,25D analogs have the HDACi-like structure replacing the 1,25D side chain. Both compounds proved to be agonists of the vitamin D receptor. Moreover, the TSA-substituted compound, called triciferol, effectively induced a-tubulin as well as histones acetylation. This study underlines the potential of combining 1,25D and TSA in cancer treatment, and reveals that bi-functional 1,25D analogs can be produced with potentially enhanced therapeutic activity.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 87 pages. Includes vita. Includes bibliographical references.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed on June 24, 2009). Includes bibliographical references.