About this Journal Submit a Manuscript Table of Contents
Evidence-Based Complementary and Alternative Medicine
Volume 2012 (2012), Article ID 726025, 15 pages
http://dx.doi.org/10.1155/2012/726025
Research Article

Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

1Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
2Cytometry Core Facility, Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany

Received 10 July 2012; Accepted 7 September 2012

Academic Editor: Ke Liu

Copyright © 2012 Benjamin Wiench et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, “Global cancer statistics,” CA: Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69–90, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Fulda and K. M. Debatin, “Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy,” Oncogene, vol. 25, no. 34, pp. 4798–4811, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. P. Li, D. Nijhawan, I. Budihardjo et al., “Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade,” Cell, vol. 91, no. 4, pp. 479–489, 1997. View at Scopus
  5. S. Fulda, L. Galluzzi, and G. Kroemer, “Targeting mitochondria for cancer therapy,” Nature Reviews Drug Discovery, vol. 9, no. 6, pp. 447–464, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. P. S. Brookes, Y. Yoon, J. L. Robotham, M. W. Anders, and S. S. Sheu, “Calcium, ATP, and ROS: a mitochondrial love-hate triangle,” American Journal of Physiology—Cell Physiology, vol. 287, no. 4, pp. C817–C833, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. J. S. Modica-Napolitano and K. K. Singh, “Mitochondrial dysfunction in cancer,” Mitochondrion, vol. 4, no. 5-6, pp. 755–762, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. V. Gogvadze, S. Orrenius, and B. Zhivotovsky, “Mitochondria in cancer cells: what is so special about them?” Trends in Cell Biology, vol. 18, no. 4, pp. 165–173, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. G. Chen, F. Wang, D. Trachootham, and P. Huang, “Preferential killing of cancer cells with mitochondrial dysfunction by natural compounds,” Mitochondrion, vol. 10, no. 6, pp. 614–625, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. G. Kroemer and J. Pouyssegur, “Tumor cell metabolism: cancer's achilles' heel,” Cancer Cell, vol. 13, no. 6, pp. 472–482, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. M. Brandon, P. Baldi, and D. C. Wallace, “Mitochondrial mutations in cancer,” Oncogene, vol. 25, no. 34, pp. 4647–4662, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. G. Guizzunti, E. A. Theodorakis, A. L. Yu, C. Zurzolo, and A. Batova, “Cluvenone induces apoptosis via a direct target in mitochondria: a possible mechanism to circumvent chemo-resistance?” Investigational New Drugs, vol. 30, no. 5, pp. 1841–1848, 2012.
  13. X. Chen, L. Yang, J. J. Oppenheim, and O. M. Z. Howard, “Cellular pharmacology studies of shikonin derivatives,” Phytotherapy Research, vol. 16, no. 3, pp. 199–209, 2002. View at Publisher · View at Google Scholar · View at Scopus
  14. U. Sankawa, Y. Ebizuka, T. Miyazaki, Y. Isomura, and H. Otsuka, “Antitumor activity of shikonin and its derivatives,” Chemical and Pharmaceutical Bulletin, vol. 25, no. 9, pp. 2392–2395, 1977. View at Scopus
  15. X. P. Guo, X. Y. Zhang, and S. D. Zhang, “Clinical trial on the effects of shikonin mixture on later stage lung cancer,” Zhong Xi Yi Jie He Za Zhi, vol. 11, no. 10, pp. 598–580, 1991. View at Scopus
  16. J. Chen, J. Xie, Z. Jiang, B. Wang, Y. Wang, and X. Hu, “Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2,” Oncogene, vol. 30, pp. 4297–4306, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. T. Efferth, A. Sauerbrey, A. Olbrich et al., “Molecular modes of action of artesunate in tumor cell lines,” Molecular Pharmacology, vol. 64, no. 2, pp. 382–394, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. C. R. Thoma, A. Matov, K. L. Gutbrodt et al., “Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability,” Journal of Cell Biology, vol. 190, no. 6, pp. 991–1003, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. J. O'Brien, I. Wilson, T. Orton, and F. Pognan, “Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity,” European Journal of Biochemistry, vol. 267, no. 17, pp. 5421–5426, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. J. Eberwine, H. Yeh, K. Miyashiro et al., “Analysis of gene expression in single live neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 7, pp. 3010–3014, 1992. View at Scopus
  21. B. Wiench, T. Eichhorn, B. Korn, M. Paulsen, and T. Efferth, “Utilizing inherent fluorescence of therapeutics to analyze real-time uptake and multi-parametric effector kinetics,” Methods, vol. 57, no. 3, pp. 376–382, 2012.
  22. D. A. Bass, J. W. Parce, and L. R. Dechatelet, “Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation,” Journal of Immunology, vol. 130, no. 4, pp. 1910–1917, 1983. View at Scopus
  23. A. Cossarizza, R. Ferraresi, L. Troiano et al., “Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry,” Nature Protocols, vol. 4, no. 12, pp. 1790–1797, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. K. W. Kohn, L. C. Erickson, R. A. G. Ewig, and C. A. Friedman, “Fractionation of DNA from mammalian cells by alkaline elution,” Biochemistry, vol. 15, no. 21, pp. 4629–4637, 1976. View at Scopus
  25. B. Epe, M. Pflaum, and S. Boiteux, “DNA damage induced by photosensitizers in cellular and cell-free systems,” Mutation Research, vol. 299, no. 3-4, pp. 135–145, 1993. View at Scopus
  26. R. M. Paredes, J. C. Etzler, L. T. Watts, W. Zheng, and J. D. Lechleiter, “Chemical calcium indicators,” Methods, vol. 46, no. 3, pp. 143–151, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. C. C. Liang, A. Y. Park, and J. L. Guan, “In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro,” Nature Protocols, vol. 2, no. 2, pp. 329–333, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. T. Gebäck, M. M. P. Schulz, P. Koumoutsakos, and M. Detmar, “TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays,” BioTechniques, vol. 46, no. 4, pp. 265–274, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. A. J. Kowaltowski, N. C. de Souza-Pinto, R. F. Castilho, and A. E. Vercesi, “Mitochondria and reactive oxygen species,” Free Radical Biology and Medicine, vol. 47, no. 4, pp. 333–343, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. I. C. Chang, Y. J. Huang, T. I. Chiang, C. W. Yeh, and L. S. Hsu, “Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells,” Biological and Pharmaceutical Bulletin, vol. 33, no. 5, pp. 816–824, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. T. R. Henry and K. B. Wallace, “Differential mechanisms of induction of the mitochondrial permeability transition by quinones of varying chemical reactivities,” Toxicology and Applied Pharmacology, vol. 134, no. 2, pp. 195–203, 1995. View at Publisher · View at Google Scholar · View at Scopus
  32. W. Eiberger, B. Volkmer, R. Amouroux, C. Dhérin, J. P. Radicella, and B. Epe, “Oxidative stress impairs the repair of oxidative DNA base modifications in human skin fibroblasts and melanoma cells,” DNA Repair, vol. 7, no. 6, pp. 912–921, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. A. M. Oltra, F. Carbonell, C. Tormos, A. Iradi, and G. T. Sáez, “Antioxidant enzyme activities and the production of MDA and 8-oxo-dG in chronic lymphocytic leukemia,” Free Radical Biology and Medicine, vol. 30, no. 11, pp. 1286–1292, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. Z. Darzynkiewicz, S. Bruno, G. Del Bino et al., “Features of apoptotic cells measured by flow cytometry,” Cytometry, vol. 13, no. 8, pp. 795–808, 1992. View at Publisher · View at Google Scholar · View at Scopus
  35. R. C. Taylor, S. P. Cullen, and S. J. Martin, “Apoptosis: controlled demolition at the cellular level,” Nature Reviews Molecular Cell Biology, vol. 9, no. 3, pp. 231–241, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Watanabe, J. Noritake, and K. Kaibuchi, “Regulation of microtubules in cell migration,” Trends in Cell Biology, vol. 15, no. 2, pp. 76–83, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. T. Stepanova, J. Slemmer, C. C. Hoogenraad et al., “Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein),” Journal of Neuroscience, vol. 23, no. 7, pp. 2655–2664, 2003. View at Scopus
  38. M. R. Diehl, K. Zhang, H. J. Lee, and D. A. Tirrell, “Engineering cooperativity in biomotor-protein assemblies,” Science, vol. 311, no. 5766, pp. 1468–1471, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. E. T. O'Brien, E. D. Salmon, and H. P. Erickson, “How calcium causes microtubule depolymerization,” Cell Motility and the Cytoskeleton, vol. 36, pp. 125–135, 1997.
  40. W. Han, L. Li, S. Qiu et al., “Shikonin circumvents cancer drug resistance by induction of a necroptotic death,” Molecular Cancer Therapeutics, vol. 6, no. 5, pp. 1641–1649, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Fujii, Y. Yamashita, Y. Arima, M. Nagashima, and H. Nakano, “Induction of topoisomerase II-mediated DNA cleavage by the plant naphthoquinones plumbagin and shikonin,” Antimicrobial Agents and Chemotherapy, vol. 36, no. 12, pp. 2589–2594, 1992. View at Scopus
  42. Y. W. Cheng, C. Y. Chang, K. L. Lin, C. M. Hu, C. H. Lin, and J. J. Kang, “Shikonin derivatives inhibited LPS-induced NOS in RAW 264.7 cells via downregulation of MAPK/NF-κB signaling,” Journal of Ethnopharmacology, vol. 120, no. 2, pp. 264–271, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. Z. Wu, L. Wu, L. Li, S. I. Tashiro, S. Onodera, and T. Ikejima, “p53-mediated cell cycle arrest and apoptosis Induced by Shikonin via a Caspase-9-Dependent Mechanism in Human Malignant Melanoma A375-S2 Cells,” Journal of Pharmacological Sciences, vol. 94, no. 2, pp. 166–176, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. H. Yang, P. Zhou, H. Huang et al., “Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo,” International Journal of Cancer, vol. 124, no. 10, pp. 2450–2459, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. S. C. Chiu and N. S. Yang, “Inhibition of tumor necrosis factor-α through selective blockade of Pre-mRNA splicing by shikonin,” Molecular Pharmacology, vol. 71, no. 6, pp. 1640–1645, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Buzzai, D. E. Bauer, R. G. Jones et al., “The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation,” Oncogene, vol. 24, no. 26, pp. 4165–4173, 2005. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Chendong, J. Sudderth, D. Tuyen, R. G. Bachoo, J. G. McDonald, and R. J. DeBerardinis, “Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling,” Cancer Research, vol. 69, no. 20, pp. 7986–7993, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. S. J. Ralph and J. Neuzil, “Mitochondria as targets for cancer therapy,” Molecular Nutrition & Food Research, vol. 53, no. 1, pp. 9–28, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Iyanagi and I. Yamazaki, “One-electron-transfer reactions in biochemical systems V. Difference in the mechanism of quinone reduction by the NADH dehydrogenase and the NAD(P)H dehydrogenase (DT-diaphorase),” Biochimica et Biophysica Acta, vol. 216, no. 2, pp. 282–294, 1970. View at Scopus
  50. D. N. Criddle, S. Gillies, H. K. Baumgartner-Wilson et al., “Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells,” Journal of Biological Chemistry, vol. 281, no. 52, pp. 40485–40492, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. S. P. Jackson and J. Bartek, “The DNA-damage response in human biology and disease,” Nature, vol. 461, no. 7267, pp. 1071–1078, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. G. Kroemer, L. Galluzzi, and C. Brenner, “Mitochondrial membrane permeabilization in cell death,” Physiological Reviews, vol. 87, no. 1, pp. 99–163, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. K. Gong and W. Li, “Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: a potential new treatment for hepatocellular carcinoma,” Free Radical Biology & Medicine, vol. 51, pp. 2259–2271, 2011.