Rosuvastatin Induces ROS-mediated Apoptosis in Human Prostate Cancer PC-3 Cells

Rosuvastatin이 유도하는 ROS가 전립선암 PC-3 세포주의 세포사멸 유도에 미치는 영향

Choi, Hyeun Deok;Baik, Jong Jin;Kim, Sang Hun;Yu, Sun Nyoung;Chun, Sung Hak;Kim, Young Wook;Nam, Hyo Won;Kim, Kwang Youn;Ahn, Soon Cheol

  • Received : 2015.12.09
  • Accepted : 2016.02.02
  • Published : 2016.04.30


Statins, the inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, are widely used in treatments of hypercholesterolemia and newly known as anti-cancer effect of various cancer cells. Recently, several studies suggested that reactive oxygen species (ROS) play a critical role on cell death signaling. However, mechanism of ROS by rosuvastatin is currently unclear. This study aimed to explore the molecular mechanism of apoptosis by rosuvastatin in human prostate cancer PC-3 cells. Cell viability and apoptosis-related protein expression were measured by MTT assay and western blotting, respectively. In addition, the levels of apoptosis and ROS were analyzed. The results showed that rosuvastatin dramatically reduced cell viability in a dose- and time-dependent manner. We confirmed that rosuvastatin induced apoptosis through reduction of procaspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) in PC-3 cells. In addition, rosuvastatin stimulated ROS production in a dose-dependent manner and pre-treatment with N-acetylcysteine (NAC), a ROS scavenger, significantly recovered rosuvastatin-induced ROS and apoptosis. Thus, we concluded that rosuvastain induces apoptosis through generation of ROS in human prostate cancer PC-3 cells and provides a promising approach to improve the efficacy of cancer therapy.


Apoptosis;human prostate cancer PC-3 cells;N-acetylcysteine;reactive oxygen species;rosuvastatin


  1. Agarwal, B., Bhendwal, S., Halmos, B., Moss, S. F., Ramey, W. G. and Holt, P. R. 1999. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin. Cancer Res. 5, 2223-2229.
  2. Buttke, T. M. and Sandstrom, P. A. 1994. Oxidative stress as a mediator of apoptosis. Immunol. Today 15, 7-10.
  3. Cafforio, P., Dammacco, F., Gernone, A. and Silvestris, F. 2005. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 26, 883-891.
  4. Cardwell, C. R., Mc Menamin, Ú., Hughes, C. M. and Murray, L. J. 2015. Statin use and survival from lung cancer: A population-based cohort study. Cancer Epidemiol. Biomarkers Prev. 24, 833-841.
  5. Corsini, A., Pazzucconi, F., Arnaboldi, L., Pfister, P., Fumagalli, R., Paoletti, R. and Sirtori, C. R. 1998. Direct effects of statins on the vascular wall. J. Cardiovasc. Pharmacol. 31, 773-778.
  6. De Backer, G., Ambrosionie, E., Borch-Johnsen, K., Brotons, C., Cifkova, R., Dallongeville, J. and et al. 2003. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur. J. Cardiovasc. Prev. Rehabil. 10, S1-S78.
  7. Dimitroulakos, J., Thai, S., Wasfy, G. H., Hedley, D. W., Minden, M. D. and Penn, L. Z. 2000. Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. Leuk. Lymphoma 40, 167-178.
  8. Donovan, M. and Cotter, T. G. 2004. Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death. Biochim. Biophys. Acta 1644, 133-147.
  9. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. 2001. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Jama 285, 2486.
  10. Grundy, S. M., Cleeman, J. I., Merz, C. N. B., Brewer, H. B., Clark, L. T., Hunninghake, D. B., Pasternak, R. C., Smith, S. C. and Stone, S. N. 2004. Implications of recent clinical trials for the national cholesterol education program adult treatment panel III guidelines. J. Am. Coll. Cardiol. 44, 720-732.
  11. Hartwell, L. H. and Kastan, M. B. 1994. Cell cycle control and cancer. Science 266, 1821-1828.
  12. Herman-Antosiewicz, A. and Singh, S. V. 2004. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review. Mutat. Res. 555, 121-131.
  13. Huerta, S., Goulet, E. J. and Livingston, E. H. 2006. Colon cancer and apoptosis. Am. J. Surg. 191, 517-526.
  14. Istvan, E. S. and Deisenhofer, J. 2001. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160-1164.
  15. Jung, K. W., Won, Y. J., Kong, H. J., Oh, C. M., Seo, H. G. and Lee, J. S. 2013. Prediction of cancer incidence and mortality in Korea, 2013. Cancer Res. Treat. 45, 15.
  16. Kamata, H. and Hirata, H. 1999. Redox regulation of cellular signalling. Cell. Signal. 11, 1-14.
  17. Kawiak, A., Zawacka-Pankau, J., Wasilewska, A., Stasilojc, G., Bigda, J. and Lojkowska, E. 2012. Induction of apoptosis in HL-60 cells through the ROS-mediated mitochondrial pathway by ramentaceone from Drosera aliciae. J. Nat. Prod. 75, 9-14.
  18. Kim, G. H., Lee, M. H., Han, M. H., Park, C., Hong, S. H. and Choi, Y. H. 2013. Induction of apoptosis by citri pericarpium methanol extract through reactive oxygen species generation in U937 human leukemia cells. J. Life Sci. 23, 1057-1063.
  19. Klotz, L. 2013. Active surveillance for prostate cancer: Overview and update. Curr. Treat. Options Oncol. 14, 97-108.
  20. Kong, E. H., Kim, Y. J., Kim, Y. J., Cho, H. J., Yu, S. N., Kim, K. Y, Chang, J. H. and Ahn, S. C. 2008. Piplartine induces caspase-mediated apoptosis in PC-3 human prostate cancer cells. Oncol. Rep. 20, 785-792.
  21. Lapenna, S. and Giordano, A. 2009. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discovery 8, 547-566.
  22. Lavrik, I. N., Golks, A. and Krammer, P. H. 2005. Caspases: pharmacological manipulation of cell death. J. Clin. Invest. 115, 2665.
  23. Lee, Y. K., Hwang, J. T., Kwon, D. Y., Surh, Y. J. and Park, O. J. 2010. Induction of apoptosis by quercetin is mediated through AMPKα1/ASK1/p38 pathway. Cancer Lett. 292, 228-236.
  24. Li, X. and Darzynkiewicz, Z. 2000. Cleavage of poly (ADP-ribose) polymerase measured in situ in individual cells: relationship to DNA fragmentation and cell cycle position during apoptosis. Exp. Cell Res. 255, 125-132.
  25. Ling, Y. H., Liebes, L., Zou, Y. and Perez-Soler, R. 2003. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J. Biol. Chem. 278, 33714-33723.
  26. Malumbres, M. and Barbacid, M. 2009. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer 9, 153-166.
  27. Marcelli, M., Cunningham, G. R., Haidacher, S. J., Padayatty, S. J., Sturgis, L., Kagan, C. and Denner, L. 1998. Caspase-7 is activated during lovastatin-induced apoptosis of the prostate cancer cell line LNCaP. Cancer Res. 58, 76-83.
  28. Maron, D. J., Fazio, S. and Linton, M. F. 2000. Current perspectives on statins. Circulation 101, 207-213.
  29. Moungjaroen, J., Nimmannit, U., Callery, P. V., Wang, L., Azad, N., Lipipun, V., Chanvorachote, P. and Rojanasakul, Y. 2006. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J. Pharmacol. Exp. Ther. 319, 1062-1069.
  30. Newman, D. J. and Cragg, G. M. 2007. Natural products as sources of new drugs over the Last 25 Years. J. Nat. Prod. 70, 461-477.
  31. Park, H. J., Jin, S. J., Oh, Y. N., Kim, B. W. and Kwon, H. J. 2015. Induction of apoptosis by methanol extract of Endlicheria anomala in human lung and liver cancer cells. J. Life Sci. 25, 441-449.
  32. Rossé, T., Olivier, R., Monney, L., Rager, M., Conus, S., Fellay, I., Jansen, B. and Borner, C. 1998. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature 391, 496-499.
  33. Siegel, R., Miller, K. and Jemal, A. 2015. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5-29
  34. Van Aelst, L. and D’Souza-Schorey, C. 1997. Rho GTPases and signaling networks. Genes Dev. 11, 2295-2322.
  35. Wang, I. K., Lin-Shiau, S. Y. and Lin, J. K. 2000. Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. Pharmacol. Toxicol. 86, 83-91.
  36. Zimmermann, K. C., Bonzon, C. and Green, D. R. 2001. The machinery of programmed cell death. Pharmacol. Ther. 92, 57-70.