Simvastatin Inducing Pc3 Prostate Cancer Cell Necrosis Mediated By Calcineurin And Mitochondrial Dysfunction

In the present study we analyzed the mechanisms of simvastatin toxicity for the PC3 human prostate cancer cell line. At 10 μM, simvastatin induced principally apoptosis, which was prevented by mevalonic acid but not by cyclosporin A, the inhibitor of calcineurin and mitochondrial permeability transition (MPT). At 60 μM, simvastatin induced the necrosis of PC3 cells insensitive to mevalonic acid. Cell necrosis was preceded by a threefold increase in cytosolic free Ca 2+ concentration and a significant decrease in both respiration rate and mitochondrial membrane potential. Both mitochondrial dysfunction and necrosis were sensitive to the compounds cyclosporin A and bongkrekic acid, as well as the calcineurin inhibitor FK506. We have concluded that simvastatin-induced PC3 cells apoptosis is dependent on 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibition and independent of MPT, whereas necrosis is dependent on mitochondrial dysfunction caused, at least in part, by calcineurin. © 2008 Springer Science+Business Media, LLC.404307314Almeida, S., Domingues, A., Rodrigues, L., (2004) Neurobiol Dis, 17, pp. 435-444Ankarcrona, M., Dypbukt, J.M., Orrenius, S., (1996) FEBS Lett, 394, pp. 321-324Campos, C.B.L., Degasperi, G.R., Pacífico, D.S., (2004) Biochem Pharmacol, 68, pp. 2197-2206Collins, R., Armitage, J., Parish, S., (2003) Lancet, 361, pp. 2005-2016Dawson, T.M., Steiner, J.P., Dawson, V.L., (1993) Proc Natl Acad Sci U S a, 90, pp. 9808-9812Degasperi, G.R., Velho, J.A., Zecchin, K.G., (2006) J Bioenerg Biomembr, 38, pp. 1-10Demierre, M.-F., Higgins, P.D.R., Gruber, S.B., (2005) Nat Rev Cancer, 5, pp. 930-942Ghosh, P.M., Ghosh-Choudhury, N., Moyer, M.L., (1999) Oncogene, 18, pp. 4120-4130Gunter, K.K., Gunter, T.E., (1994) J Bioenerg Biomembr, 26, pp. 471-485Halestrap, A.P., Brenner, C., (2003) Curr Med Chem, 10, pp. 1507-1525Halestrap, A.P., Connern, C.P., Griffths, E.J., (1997) Mol Cell Biochem, 174, pp. 167-172Hara, M.R., Snyder, S.H., (2007) Toxicol, 47, pp. 117-141Hindler, K., Cleeland, C.S., Rivera, E., (2006) Oncologist, 11, pp. 306-315Holden, M.J., Sze, H., (1989) Plant Physiol, 91, pp. 1296-1302Hoque, A., Chen, H., Xu, X.C., (2008) Cancer Epidemiol Biomarkers Prev, 17, pp. 88-94Kowaltowski, A.J., Castilho, R.F., Vercesi, A.E., (2001) FEBS Lett, 495, pp. 12-15Kroemer, G., Galluzi, L., Brenner, C., (2007) Physiol Rev, 87, pp. 99-163Li, Y.C., Park, M.J., Ye, S.-K., (2006) Am J Pathol, 168, pp. 1107-1118Liu, J., Farmer, J.D.J., Lane, W.S., Friedman, J., (1991) Cell, 66, pp. 807-815Manev, H., Favaron, M., Candeo, P., (1993) Brain Res, 624, pp. 331-335Marcelli, M., Glenn, R.C., Haidacher, S.J., (1998) Cancer Res, 58, pp. 76-83Park, C., Lee, I., Kang, W.K., (2001) Carcinogenesis, 22, pp. 1727-1731Platz, E.A., Leitzmann, M.F., Visvanathan, K., (2006) J Natl Cancer Inst, 98, pp. 1819-1825Rao, S., Porter, D.C., Chen, X., (1999) Proc Natl Acad Sci U S a, 96, pp. 7797-7802Shepherd, J., Cobbe, S.M., Ford, I., (1995) N Engl J Med, 333, pp. 1301-1307Shibasaki, F., McKeon, F., (1995) Cell Biol, 131, pp. 735-743Sivaprasad, U., Abbas, T., Dutta, A., (2006) Mol Cancer Ther, 5, pp. 2310-2316Springer, J.E., Azbill, R.D., Nottingham, S.A., (2000) J Neurosci, 20, pp. 7246-7251Ukomadu, C., Dutta, A., (2003) J Biol Chem, 278, pp. 4840-4846Velho, J.A., Okanobo, H., Degasperi, G.R., (2006) Toxicology, 219, pp. 124-132Vercesi, A.E., Kowaltowski, A.J., Oliveira, H.C.F., (2006) Front Biosc, 11, pp. 2554-2564Wang, H.G., Pathan, N., Ethell, I.M., (1999) Science, 284, pp. 339-343Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., (2001) Nat Med, 7, pp. 687-692Zecchin, K.G., Seidinger, A.L.O., Degasperi, G.R., (2007) J Bioenerg Biomembr, 39, pp. 186-19