32. Squadrito GL, Cueto R, Dellinger B, Pryor WA (2001) Quinoid redox cycling as a mechanism for sustained free radical generation by inhaled airborne particulate matter. Free Radic Biol Med 31: 1132–1138. 33. Ollinger K, Kagedal K (2002) Induction of apoptosis by redox-cycling quinones. Subcell Biochem 36: 151–170. 34. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99–163. 35. Nagy G, Koncz A, Perl A (2003) T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide. J Immunol 171: 5188–5197. 36. Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta 1757: 509–517. 37. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552: 335–344. 38. Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, et al. (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94: 325–337. 39. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, et al. (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525–535. 40. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (2002) Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochon- dria. J Biol Chem 277: 13430–13437. 41. Yin XM (2000) Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res 10: 161–167. 42. Kim BM, Hong SH (2011) Sequential caspase-2 and caspase-8 activation is essential for saikosaponin a-induced apoptosis of human colon carcinoma cell lines. Apoptosis 16: 184–197. 43. Izeradjene K, Douglas L, Tillman DM, Delaney AB, Houghton JA (2005) Reactive oxygen species regulate caspase activation in tumor necrosis factor- related apoptosis-inducing ligand-resistant human colon carcinoma cell lines. Cancer Res 65: 7436–7445. 44. Prasad V, Chandele A, Jagtap JC, Sudheer KP, Shastry P (2006) ROS-triggered caspase 2 activation and feedback amplification loop in beta-carotene-induced apoptosis. Free Radic Biol Med 41: 431–442. 45. Zuo Y, Xiang B, Yang J, Sun X, Wang Y, et al. (2009) Oxidative modification of caspase-9 facilitates its activation via disulfide-mediated interaction with Apaf-1. Cell Res 19: 449–457. 46. Pasciu V, Posadino AM, Cossu A, Sanna B, Tadolini B, et al. (2010) Akt downregulation by flavin oxidase-induced ROS generation mediates dose- dependent endothelial cell damage elicited by natural antioxidants. Toxicol Sci 114: 101–112. Antitumor Activity of Jacaranone 47. Dhawan P, Singh AB, Ellis DL, Richmond A (2002) Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor- kappaB and tumor progression. Cancer Res 62: 7335–7342. 48. Testa JR, Bellacosa A (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A 98: 10983–10985. 49. Shin SW, Seo CY, Han H, Han JY, Jeong JS, et al. (2009) 15d-PGJ2 induces apoptosis by reactive oxygen species-mediated inactivation of Akt in leukemia and colorectal cancer cells and shows in vivo antitumor activity. Clin Cancer Res 15: 5414–5425. 50. Xu J, Liu D, Songyang Z (2002) The role of Asp-462 in regulating Akt activity. J Biol Chem 277: 35561–35566. 51. Jia YT, Wei W, Ma B, Xu Y, Liu WJ, et al. (2007) Activation of p38 MAPK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury. J Immunol 179: 7808–7819. 52. Park KR, Nam D, Yun HM, Lee SG, Jang HJ, et al. (2011) beta-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/ AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett 312: 178–188. 53. Lopez-Bergami P (2011) The role of mitogen- and stress-activated protein kinase pathways in melanoma. Pigment Cell Melanoma Res 24: 902–921. 54. Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, et al. (2001) Akt down-regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. J Biol Chem 276: 30359–30365. 55. Berra E, Diaz-Meco MT, Moscat J (1998) The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J Biol Chem 273: 10792–10797. 56. Wagner EF, Nebreda AR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9: 537–549. 57. Kim BJ, Ryu SW, Song BJ (2006) JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281: 21256–21265. 58. Porras A, Zuluaga S, Black E, Valladares A, Alvarez AM, et al. (2004) P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell 15: 922–933. 59. Chang CW, Tsai WH, Chuang WJ, Lin YS, Wu JJ, et al. (2009) Procaspase 8 and Bax are up-regulated by distinct pathways in Streptococcal pyrogenic exotoxin B-induced apoptosis. J Biol Chem 284: 33195–33205. 60. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, et al. (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17: 590–603. PLoS ONE | www.plosone.org 11 June 2012 | Volume 7 | Issue 6 | e38698