Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/308210
Type: DISSERTAÇÃO
Degree Level: Mestrado
Title: Homeostase de CA2+ e função mitocondrial na morte de celulas de cancer de prostata induzida por estatinas
Title Alternative: Calcium homeostasis and mitochondrial function during death of prostate cancer cells exposed to statins
Author: Oliveira, Kivia Aparecida Pontes de
Advisor: Vercesi, Anibal Eugenio, 1946-
Abstract: Resumo: As estatinas são inibidores da 3-hidroxi-3-metilglutaril CoA (HMG-CoA) redutase usados no tratamento de hipercolesterolemia. Estudos in vitro e in vivo têm demonstrado que as estatinas podem ter efeitos anti-cancerígenos. No presente estudo analisamos os mecanismos de toxicidade de sinvastatina e de lovastatina nas linhagens de câncer de próstata LNCaP e PC-3. Curvas dose-resposta do efeito das estatinas (0,1-100 µM) sobre as células LNCaP e PC-3 mostraram efeitos similares e maior sensibilidade das células PC-3 do que das células LNCaP. Tratamentos de células PC-3 com sinvastatina 10 µM durante 48 h induziu morte principalmente por apoptose, a qual foi associada ao aumento de 3 vezes da [Ca2+]cit. Tanto a apoptose quanto o aumento da [Ca2+]cit foram prevenidos por mevalonato 100 µM presente no meio de cultura. Isso indica que a inibição da HMG-CoA redutase leva à apoptose mediada por Ca2+. Pifitrina-a, inibidor da proteína supressora tumoral p53, não preveniu apoptose em células PC-3 (p53 negativas) nem em células LNCaP (p53 positivas). Isso mostrou que a apoptose de células de câncer de próstata induzida por estatinas é independente de p53. Sinvastatina 60 µM induziu morte de células PC-3 principalmente por necrose, a qual foi associada ao aumento de 3 vezes da [Ca2+]cit e à diminuição da respiração e do potencial de membrana mitocondrial. Tanto a necrose quanto a disfunção mitocondrial foram parcialmente prevenidas pelos compostos ciclosporina A (inibidor da transição de permeabilidade mitocondrial [TPM] e da fosfatase calcineurina), FK506 (inibidor de calcineurina) e boncrecato (inibidor da TPM). O aumento da [Ca2+]cit não foi prevenido por ciclosporina A, FK506 ou boncrecato, porém a complexação de Ca2+ citossólico com BAPTA protegeu as células PC-3 da necrose, sugerindo que o aumento da [Ca2+]cit seja um dos primeiros passos no processo de necrose celular, seguido pela ativação da via de calcineurina. Conclui-se que a apoptose induzida por sinvastatina em células PC-3 seja dependente da via do mevalonato enquanto que a necrose seja dependente da via da calcineurina associada à disfunção mitocondrial

Abstract: Statins are 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors used in the treatment of hypercholesterolemia. Both in vitro and in vivo studies have demonstrated that statins may have anti-cancer effects. In the present study we analyzed the mechanisms of simvastatin and lovastatina toxicity to the human prostate cancer cell lines LNCaP and PC-3. Dose-response curves of statins (0.1-100 µM) effects upon LNCaP and PC-3 cells showed similar effects and higher sensitivity of PC-3 than LNCaP cells. Treatments of PC-3 cells with 10 µM simvastatin during 48 h induced death mainly by apoptosis, which was associated with a 3-fold increase in [Ca2+]cyt. Both apoptosis and [Ca2+]cyt increase were prevented by 100 µM mevalonate present in the culture medium. This indicates that the inhibition of HMG-CoA reductase is followed by Ca2+ mediated apoptosis. Pifithrin-a, an inhibitor of tumor suppressor p53 protein, did not prevented apoptosis either in PC-3 (p53 negative) or LNCaP (p53 positive) cells. This showed that apoptosis of prostate cancer cells induced by statins is p53 independent. At 60 µM, simvastatin induced death in PC-3 cells mainly by necrosis, which was associated with a 3-fold increase in PC-3 [Ca2+]cyt, and decrease in both respiration and mitochondrial membrane potential. Both necrosis and mitochondrial dysfunction were partially prevented by the compounds cyclosporine A (mitochondrial permeability transition [MPT] and calcineurin inhibitor), FK506 (calcineurin inhibitor), and bongkrekic acid (MPT inhibitor). Increase in [Ca2+]cyt was not prevented by cyclosporine A, FK506 or bongkrekic acid, but chelation of [Ca2+]cyt with BAPTA protected PC-3 cells from necrosis, suggesting rise in [Ca2+]cyt is one of the first steps in the process of cell necrosis and is followed by activation of the calcineurin pathway. We may conclude that simvastatin-induced apoptosis in PC-3 cells is dependent on the mevalonate pathway whereas necrosis is dependent on the calcineurin pathway associated with mitochondrial dysfunction
Subject: Próstata - Câncer
Prostata - Doenças
Morte celular
Language: Português
Editor: [s.n.]
Date Issue: 2008
Appears in Collections:FCM - Tese e Dissertação

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