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| Author(s): |
Kivia Aparecida Pontes de Oliveira
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2008-02-27 |
| Examining board members: |
Anibal Eugenio Vercesi;
Hernandes Faustino de Carvalho;
Roger Chammas
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| Advisor: | Anibal Eugenio Vercesi; Roger Frigério Castilho |
| 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 (AU) | |