The chemokine receptor CCR5 has been implicated in the pathogenesis of prostate cancer. A novel natural product, anibamine, was isolated and found to be a micromolar inhibitor of the receptor. Anibamine was used as a new anti-prostate cancer lead compound. To discover the pharmacophore, analogs of anibamine were designed using the “deconstruction-reconstruction-elaboration” approach and synthesized. The establishment of a stereoselective route to only one isomer was explored, to increase yield and eliminate elaborate purification procedures. Analogs were found to have anti-prostate cancer activity at levels higher than the parent compound. The molecular modeling studies of the deconstructed analogs indicate that due to the psuedo-symmetry of the parent compound, the binding conformation of the deconstructed analogs may not be very different from each other. All this information together may help identify a next generation lead compound for anti-prostate cancer treatment.

<p>The androgen receptor (AR) signaling axis is a well-established therapeutic target in prostate cancer, due to its central role in tumor maintenance and progression. Although patients respond initially to androgen deprivation therapies and AR antagonists, they invariably progress to a castration-resistant state. Consequently, there is an unmet need for agents that target the AR signaling axis in a unique manner. </p><p>Histone deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal (EMT) and neuroendocrine differentiation, both of which are associated with prostate cancer progression and aggressiveness. Given that 18 different HDAC isoforms have been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC inhibitors have been used in most of these studies, the relative contribution of individual HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains to be elucidated. The overarching goals of this study were to (1) determine the role of individual Class I HDACs in AR transcriptional activity and prostate cancer growth, (2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate AR target gene transcription and prostate cancer growth. </p><p>Using genetic knockdown studies and pharmacological inhibitors with isoform selectivity, we identified that HDAC3 was required for AR transcriptional activity and proliferation in cellular models of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally, we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide an explanation for the lack of success using non-selective HDAC inhibitors in clinical trials for prostate cancer.</p><p>We also assessed the role of REV-ERB alpha, an HDAC3-interacting protein, in the regulation of AR transcriptional activity and prostate cancer growth. Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we concluded that REV-ERB alpha; was required for AR target gene induction and prostate cancer growth, including models of CRPC. These studies also provide rational for targeting REV-ERB alpha; for the treatment of CRPC.</p><p>Taken together, these studies identify two novel targets in the HDAC signaling axis for the treatment of prostate cancer: HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional regulation and prostate cancer pathophysiology.</p> / Dissertation

Many pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that regulation of NOTCH3 by the p38 MAPK family (hereafter p38-MAPK), via MYC, is required for luminal differentiation. Inhibition (SB202190 and BIRB796) or knockdown of p38a (also known as MAPK14) and/or p38d (also known as MAPK13) prevented proper differentiation. Additionally, treatment with a gamma-secretase inhibitor (RO4929097) or knockdown of NOTCH1 and/or NOTCH3 greatly impaired differentiation and caused luminal cell death. Constitutive p38-MAPK activation through MKK6(CA) increased NOTCH3 (but not NOTCH1) mRNA and protein levels, which was diminished upon MYC inhibition (10058-F4 and JQ1) or knockdown. Furthermore, we validated two NOTCH3 enhancer elements through a combination of enhancer (e) RNA detection (BruUV-seq) and luciferase reporter assays. Finally, we found that the NOTCH3 mRNA half-life increased during differentiation or upon acute p38-MAPK activation. These results reveal a new connection between p38-MAPK, MYC and NOTCH signaling, demonstrate two mechanisms of NOTCH3 regulation and provide evidence for NOTCH3 involvement in prostate luminal cell differentiation.

Background: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. Methods: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. Results: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile (1 vs. Quartile) (4) = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile (4) = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m(2)), but not among men with high BMI (>= 27.8 kg/m(2)). Interactions of race and BMI with vitamin D intake were significant (P-Interaction < 0.05). Conclusion: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Upplevelsen av livskvalitet hos män med prostatacancer – en litteraturstudie                                         Abstrakt Bakgrund: Prostatacancer är den vanligast förekommande cancerformen bland män i Sverige. Många män lever med biverkningar efter behandlingen, vilket kan påverka deras liv negativt och hur de upplever sin livskvalitet. Syfte: Syftet var att belysa upplevelsen av livskvalitet hos män med prostatacancer. Metod: En litteraturstudie där åtta vetenskapliga artiklar med kvalitativ ansats har granskats, sammanställts och analyserats. Resultat: Tre huvudkategorier med sex kategorier identifierades: Bemästrande av situationen – Strävan efter väbefinnande genom kontroll, Insikt i sjukdomens påverkan. Adaption till livssituation – En förändringsprocess i livet, En kamp för sinnesro. Manlig identitet – Den förändrade sexualiteten påverkar identiteten, Relationer som stöd.   Konklusion: Upplevelsen av livskvalitet varierar från individ till individ och påverkas av bl.a. biverkningar efter behandling och synen på sin livssituation. Författarna tror att litteraturstudien kan medvetandegöra sjuksköterskor om vilken påverkan prostatacancer har på männens livskvalitet. Genom att ställa personliga frågor kan sjuksköterskan ge god vård utifrån varje persons individuella behov.   Nyckelord: Prostatacancer, livskvalitet, män, anpassning / The experience of quality of life in men with prostate cancer – A literature study   Abstract Background: Prostate cancer is the most common cancer among men in Sweden. Many men live with treatment related side effects which can cause a negative effect on their lives and the experience of their quality of life. Aim: The aim was to illuminate the experience of the quality of life in men with prostate cancer. Method: A literature study of eight articles with qualitative approach. The articles result have been reviewed, compiled and analyzed. Results: Three main categories and six categories were identified: Control of the situation – quest for wellbeing through control, insight in the impact of the disease. Adaptation to life situation – a reconstruction of life, a struggle for peace of mind. Male identity – the altered sexuality affects the identity, the support of relationships. Conclusion: The experience of quality of life varies between individuals and is affected by side effects after treatment and the way they are looking at their life situation. The authors believe that this literature study can raise awareness among nurses regarding the impact prostate cancer has on men’s quality of life. By asking personal questions the nurse can provide good nursing care based on each person’s individual need.   Keywords: Prostate cancer, quality of life, men, adaptation

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Orientador: Luis Antonio Justulin Junior / Resumo: A próstata é uma glândula acessória do sistema genital masculino e, além da dependência androgênica para o seu desenvolvimento e homeostasia, é influenciada por hormônios não esteróides, entre eles a prolactina (PRL). Estudos em modelos animais demonstraram que a PRL pode atuar com efeito anabólico sobre a glândula prostática. Assim, nosso objetivo foi investigar os efeitos da modulação de PRL sobre o desenvolvimento e maturação da próstata ventral (PV) de ratos. Foram utilizados ratos machos Sprague Dawley (DPN 90) divididos em 6 grupos (n=6): Grupo controle (CT): receberam solução salina; Prolactina (PRL): Prolactina (0,3mg/kg); Bromocriptiona (BR): inibidor de PRL (0,4mg/kg). Todos os animais foram submetidos diariamente (via subcutânea) do dia pós-natal 12 (DPN12) até os DPN 21 ou 35. Os animais foram anestesiados, pesados e posteriormente foram eutanasiados. O sangue e os lobos da PV foram coletados, pesados e processados para análises morfológicas, de western blot (WB) e RT qPCR. O tratamento com PRL induziu aumento de peso corpóreo dos animais no DPN35 comparado aos outros grupos. Histologicamente houve maior acumulo de screção no lúmen e diminuição do compartimento epitelial nos grupos PRL e BR comparados ao CT no DPN35. A reação imunohistoquímica para Ki67 demonstrou aumento de células proliferativas nos grupos tratados com PRL. A quantificação de PCNA confirmou estes dados, com aumento significante no grupo PRL35. A intensidade de reação imunohistoquímica para AR fo... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Resistance of various cancers to conventional therapies including radio- and chemo- therapy is one of the most investigated phenomena in the molecular and clinical oncology. Recurrent disease is characterized by the presence of metastases, which are responsible for 90% of cancer-related mortality. Fractionated ionizing radiation (fIR) combined with surgery or hormone therapy represent the first-choice treatment for medium to high risk localized prostate carcinoma (PCa). In PCa, the failure of radiotherapy (RT) is often caused by radioresistance and further dissemination of escaping (surviving) cells. To investigate the radioresistance-associated phenotype, we exposed four metastasis- derived human PCa cell lines (DU145, PC-3, LNCaP, and 22RV1) to clinically relevant daily fractions of ionizing radiation (fIR; 35 doses of 2 Gy) resulting in generation of two surviving populations: adherent senescent-like cells expressing common senescence-associated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2, and Nanog. While the radioresistant adherent cells were capable to resume proliferation shortly after the end of irradiation, the non- adherent cells started to proliferate only after their reattachment...

Resumo: O câncer de próstata e a hiperplasia prostática benigna são as duas principais afecções do sistema genital masculino após a quinta década de vida. Além de aspectos étnicos, etários, genéticos, estudos sobre a contaminação ambiental por agentes químicos carcinogênicos, dos hábitos alimentares e do estilo de vida vêm adquirindo importância no entendimento das causas destas afecções. A exposição a contaminantes ambientais, tais como o cádmio e a ingestão de bebidas contendo cafeína têm sido associados com o aparecimento do câncer de próstata e com a hiperplasia prostática benigna, respectivamente. Além disso, existem evidências experimentais de que a exposição da próstata em períodos críticos da sua morfogênese e de rápido crescimento a disruptores endócrinos pode gerar alterações permanentes que levarão ao aparecimento de afecções nos indivíduos adultos e idosos. Neste sentido, por exemplo, a partir da puberdade é comum os homens adquirirem o hábito de fumar e/ou de ingerir bebidas estimulantes, estando, portanto, expostos ao cádmio, presente na fumaça do cigarro, e/ou a cafeína, presente nas bebidas. Desta forma, este trabalho avaliou os efeitos, isolados e combinados, do cádmio e da cafeína, em baixas concentrações, sobre a morfologia e fisiologia da próstata de ratos púberes. Para isto, ratos Wistar com 60 dias de idade foram divididos em quatro grupos (n=15), os quais receberam, via oral, na água de beber, pelo período de 30 dias: Água, Cádmio (10ppm), Cafeína (10mg/l) ou Cafeína+Cádmio, e as próstatas dorsolaterais e ventrais foram processadas histologicamente e foram feitas análises morfológicas, citoquímicas para fibras de colágeno, morfométricas e imunocitoquímicas. Também foram determinadas as concentrações plasmáticas de cádmio e testosterona e intra-prostática de cádmio no... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The prostate cancer and the benign prostate hyperplasia are the main male genitourinary system diseases after the fifty. Besides ethic, age and genetic aspects, studies about environmental contamination, diet and life stile have also emerged as important factors involved in the etiology of these diseases. The exposure to cadmium and the intake of caffeine-containing beverage have been associated with appearing of the prostate cancer and benign prostate hyperplasia, respectively. Furthermore, there are experimental evidences that prostate exposures to endocrine disruptors during a critic period of its morphogenesis and growth may influence the onset of late-life disease. In this sense, for example, from puberty on, many males became smokers and/or start to intake energetic beverage or even yet coffee, thus being exposed to cadmium, from cigarettes and/or to caffeine, from beverage. So, here we investigated the effects of cadmium and caffeine, isolated or combined, in low doses, on rat prostate morphology during puberty. For this, male Wistar rats (n=60), 2 months-old, were divided into four experimental groups (n=15), that received by drinking water and during 30 days: tap water, cadmium (10ppm), caffeine (10ppm), cadmium plus caffeine. The prostatic lobes ventral and dorsolateral were dissected out, weighted and processed for histology. It were made morphological and morphometrical analyses; cytochemistry for collagen and reticular fibers and immunocytochemistry for Ki-67. It were also determined the plasma concentrations of testosterone and cadmium and the ventral lobe intraprostatic concentration of cadmium. The plasma and intraprostatic concentrations of cadmium were increased in the animals treated with cadmium and cadmium plus caffeine. In the conditions of this experiment, the exposure to these two agents did not alter significantly neither the prostatic... (Complete abstract click electronic access below) / Orientador: Sérgio Luis Felisbino / Coorientador: Antônio Francisco Godinho / Banca: Sebastião Roberto Taboga / Banca: Patrícia Aline Boer / Mestre

O acometimento por uma doença crônica como o câncer se constitui em uma ameaça à vida e tem repercussões físicas, psicológicas e sociais no decorrer da existência. No caso do câncer de próstata, sabe-se que seus tratamentos podem interferir na sexualidade masculina, causando perda do desejo sexual e disfunção erétil. Considerando esta realidade, o objetivo deste trabalho foi compreender o modo como homens com câncer de próstata vivenciam e atribuem significados à sua sexualidade. Optou-se pela metodologia da pesquisa qualitativa, na perspectiva da Fenomenologia Ontológico-Hermenêutica de Heidegger. E utilizou-se a história oral de vida como estratégia de acesso aos relatos dos colaboradores. Foram entrevistados 10 homens com câncer de próstata que foram submetidos a tratamentos, com idades entre 51 e 82 anos, pertencentes às classes econômicas D a B2. Os resultados dos relatos possibilitaram a construção de cinco categorias: 1) A temporalidade da infância e da adolescência; 2) A temporalidade da vida adulta: o casamento, a família e os relacionamentos afetivo-sexuais; 3) O adoecimento: as relações afetivo-sexuais após a vivência do câncer; 4) O horizonte do silêncio: o que vela e desvela o ser; e 5) Projeto de vida. A análise interpretativa desvelou a dor e o sofrimento desses homens ao apresentarem disfunção erétil e seqüelas no seu desempenho sexual, atributo do ideal de masculinidade advindo do sistema patriarcal. As vivências de dor remetem-se aos modos de existir autêntico e inautêntico. A inautenticidade foi observada na recusa em aceitar a facticidade da existência, ou seja, a concretude de um corpo que envelhece, adoece e deixa de responder ao desejo sexual. O acometimento pelo câncer de próstata potencializa o contato com a própria finitude, e alguns colaboradores fogem à angústia que surge quando se constata a possibilidade última e mais própria do existir: a morte. Esses homens buscam, então, os tratamentos disponíveis para a disfunção erétil e projetam seu porvir na possibilidade de voltarem a ter ereções satisfatórias, o que expressa o sonho do desempenho sexual vivido na juventude. Todavia, nessa trajetória, alguns colaboradores apresentaram um modo de existir autêntico, evidenciado pela compreensão da temporalidade de sua existência. Seus relatos desvelaram a consciência de que, por não poderem escapar à finitude, lhes resta aceitar as modificações na sexualidade e buscar vivenciá-la de acordo com seus limites e possibilidades. O modo de existir autêntico, que constitui a abertura do homem para o poder-ser-si-mesmo, foi desvelado na afetividade e no diálogo dos colaboradores com suas parceiras. Nesse momento em que os homens perdem a capacidade de ter ereções e sentem-se frágeis em sua masculinidade, se permitem expressar um aspecto fundamental da existência: a afetividade. A abertura para falar sobre si mesmo e ouvir sua parceira evidencia a dimensão do cuidado e da solicitude na relação afetivo-sexual. Os resultados deste estudo apontam para a compreensão ontológica do ser do homem com câncer de próstata na Pós-Modernidade e podem contribuir na construção de práticas de atenção à saúde mais humanizadas. / The effect for a chronic illness as cancer constitutes in a threat the life and has physical, psychological and social repercussions in elapsing of the existence. In the case of cancer of prostate, it is known that its treatment can intervene with the masculinity sexuality, causing loss of the sexual desire and erect dysfunction. Considering this reality, the objective of this work was to understand the way as men with cancer of prostate live deeply and attribute meanings to their sexuality. It was opted to the methodology of the qualitative research, in the perspective of the Martin Heidegger?s Ontological ? Hermeneutical Phenomenology. It was used verbal story of life as strategy of access to the stories of the collaborators. Ten men with cancer of prostate had been interviewed who had been submitted the treatments, with ages between 51 and 82 years, pertaining to economic classes D to B2. The results of the stories make possible the construction of five categories: 1) the temporality of infancy and the adolescence; 2) the temporality of the adult life: the affective marriage, family and sexual relationships; 3) the sickness: sexual affective relations after the experience of cancer; 4) the horizon of silence: what close and disclose the being; 5) life project. The interpretative analyzes exposed the pain and the suffering of these men when presenting erect dysfunction and aftermaths in their sexual performance, attribute of the ideal of masculinity happened of the patriarchal system. The pain experiences send the ways to it to exist authentic and fake. The fake way was observed in the refusal in accepting the fact of the existence, or either the acceptance of a body that ages, sickens and leaves to answer to the sexual desire. The effect for cancer of prostate elevates the contact with the proper end and some collaborators runs away to distresses that it appears when the last possibility is evidenced and more proper to exist: the death. These men search then, the available treatments for the erect dysfunction and project their future in the possibility to come back to have satisfactory erections, what express the dream of the lived sexual performance in youth. However, in this trajectory, some collaborators presents a way to exist authentic, evidenced for the understanding of the temporality of their existence. Their relates disclosed the conscience of that, for not being able to escape to the end, it remains to accept the modifications to them in the sexuality and in accordance with to live deeply their limits and possibilities. The way to exist authentic, that it constitutes the opening of the man to be able to be same itself, was disclosed in the affectivity and the dialogue of the collaborators with their partners. At this moment when the men lose the capacity to have erections and feel themselves fragile in their masculinity, if they allow expressing a basic aspect of the existence: the affectivity. The opening to speak about himself exactly and to hear his partner evidences the dimension of the care and the attention in the affective-sexual relation. The results of this study point with respect to the ontological understanding of the being of the man with cancer of prostate in Post-modernity and can contribute in the construction of practical of attention to health more humanized.