Papel modulador do raloxifeno durante a carcinogênese prostática em ratos
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2019-03-01
Autores
Pinho, Cristiane Figueiredo
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Universidade Estadual Paulista (Unesp)
Resumo
A capacidade de progressão do câncer de próstata para uma fase não-responsiva às terapias de privação androgênica traz à luz a importância do estudo de tratamentos adjuvantes. Pesquisas recentes apontam receptores estrogênicos como possíveis alvos terapêuticos em neoplasias, podendo ser modulados por fármacos como o Raloxifeno, atualmente utilizado na prevenção do câncer de mama e tratamento da osteoporose. Nesse contexto, o objetivo deste estudo foi avaliar os potenciais efeitos histoprotetores e antiproliferativos da terapia com Raloxifeno, durante a carcinogênese prostática. Para isso, 34 ratos Fisher 344 machos foram inoculados com o carcinógeno MNU (15 mg/kg) na cápsula dos lobos ventral e dorsolateral e receberam doses subcutâneas de cipionato de testosterona, duas vezes por semana, durante 220 dias, processo aqui denominado de Indução de Carcinogênese. Posteriormente, foram divididos em dois grupos experimentais para o período de Tratamento: grupo Raloxifeno, recebendo 10 mg/kg de peso corpóreo/dia de Raloxifeno diluído em 0,2 ml de óleo de milho durante 30 dias consecutivos; grupo Induzido, recebendo somente 0,2 ml de óleo de milho (veículo) durante 30 dias consecutivos. Outros 10 animais pertencentes ao grupo Controle receberam veículo duas vezes por semana por 220 dias para simular o processo de Indução e, posteriormente, durante 30 dias consecutivos para simular o período de Tratamento. Após a eutanásia, o sangue e as próstatas ventral e dorsolateral foram coletados para dosagem hormonal, análise histopatológica das lesões, quantificação de mastócitos, picrossirius (fibras colágenas) e imunomarcação para AR (receptor de andrógenos), α-actina e Ki67 (índice de proliferação). O protocolo de Indução foi capaz de aumentar a proliferação celular, induzir o aparecimento de lesões pré-malignas e malignas, comprometendo a camada muscular lisa periacinar e a distribuição estromal de fibras colágenas em animais Induzidos, enquanto o tratamento com Raloxifeno foi responsável pela redução desses padrões. A imunorreatividade ao AR mostrou-se mais homogênea nos grupos Controle e Raloxifeno nos dois lobos prostáticos, com maior discrepância no grupo Induzido, devido à presença dos diferentes tipos de lesões. O grupo Raloxifeno apresentou os menores níveis de testosterona sérica. Esses resultados mostraram um papel protetor do Raloxifeno sobre o microambiente prostático, atenuando as alterações que se acumulam durante o processo carcinogênico.
Prostate cancer ability to progress to a non-responsive phase to androgen deprivation therapy emphasizes the importance of study on adjuvant treatments. Recent research suggests estrogen receptors as possible therapeutic targets in neoplasias and they can be modulated by drugs such as Raloxifene, currently used in the prevention of breast cancer and treatment of osteoporosis. In this context, this study aimed to evaluate the histoprotective and antiproliferative potential effects of Raloxifene therapy during prostatic carcinogenesis. Thereunto, 34 male Fisher 344 rats were inoculated with the MNU carcinogen (15 mg / kg) in the ventral and dorsolateral lobe capsule and received subcutaneous doses of testosterone cypionate twice a week for 220 days. Subsequently, they were divided into two experimental groups: Raloxifene group, receiving 10 mg/kg of body weight/day of Raloxifene diluted in 0.2 ml of corn oil for 30 consecutive days; Induced group, receiving only 0.2 ml corn oil (vehicle) for 30 consecutive days. Another 10 animals belonging to the Control group received vehicle twice a week for 220 days to simulate the induction process and subsequently for 30 consecutive days to simulate the treatment period. After euthanasia, blood and the ventral and dorsolateral prostate lobes were collected for hormonal dosage, histopathological analysis of the lesions, quantification of mast cells, picrosirius (collagen fibers) and immunostaining for AR (androgen receptor), α-actin and Ki67 (proliferation index). Tumor induction protocol was able to increase cell proliferation, induce the appearance of premalignant and malignant lesions, compromising periacinar smooth muscle layer and stromal distribution of collagen fibers in Induced animals, whereas treatment with Raloxifene was responsible for reducing these patterns. AR immunoreactivity was more homogeneous in Control and Raloxifene groups for all prostate lobes, with greater discrepancy in the Induced group due to the presence of lesions. Raloxifene group had the lowest levels of serum testosterone. These results showed a protective role of Raloxifene on the prostatic microenvironment, attenuating the alterations that accumulate during the carcinogenic process.
Prostate cancer ability to progress to a non-responsive phase to androgen deprivation therapy emphasizes the importance of study on adjuvant treatments. Recent research suggests estrogen receptors as possible therapeutic targets in neoplasias and they can be modulated by drugs such as Raloxifene, currently used in the prevention of breast cancer and treatment of osteoporosis. In this context, this study aimed to evaluate the histoprotective and antiproliferative potential effects of Raloxifene therapy during prostatic carcinogenesis. Thereunto, 34 male Fisher 344 rats were inoculated with the MNU carcinogen (15 mg / kg) in the ventral and dorsolateral lobe capsule and received subcutaneous doses of testosterone cypionate twice a week for 220 days. Subsequently, they were divided into two experimental groups: Raloxifene group, receiving 10 mg/kg of body weight/day of Raloxifene diluted in 0.2 ml of corn oil for 30 consecutive days; Induced group, receiving only 0.2 ml corn oil (vehicle) for 30 consecutive days. Another 10 animals belonging to the Control group received vehicle twice a week for 220 days to simulate the induction process and subsequently for 30 consecutive days to simulate the treatment period. After euthanasia, blood and the ventral and dorsolateral prostate lobes were collected for hormonal dosage, histopathological analysis of the lesions, quantification of mast cells, picrosirius (collagen fibers) and immunostaining for AR (androgen receptor), α-actin and Ki67 (proliferation index). Tumor induction protocol was able to increase cell proliferation, induce the appearance of premalignant and malignant lesions, compromising periacinar smooth muscle layer and stromal distribution of collagen fibers in Induced animals, whereas treatment with Raloxifene was responsible for reducing these patterns. AR immunoreactivity was more homogeneous in Control and Raloxifene groups for all prostate lobes, with greater discrepancy in the Induced group due to the presence of lesions. Raloxifene group had the lowest levels of serum testosterone. These results showed a protective role of Raloxifene on the prostatic microenvironment, attenuating the alterations that accumulate during the carcinogenic process.
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Palavras-chave
Carcinogênese, Próstata, Raloxifeno, Lesões histopatológicas, Carcinogenesis, Histopathological lesions, Prostate, Raloxifene