Dioscin induces cancer cell apoptosis through elevated oxidative stress mediated by downregulation of peroxiredoxins.

Dioscin has been shown to promote anticancer activity against several forms of cancers. However, its detailed molecular mechanisms have not been clearly clarified.In this study, we demonstrate that dioscin induces apoptosis in cancer cells through the induction of oxidative stress. Treatment with cancer cells in vitro with dioscin resulted in rapid generation of reactive oxygen species (ROS) and the induction of mitochondrial pathway apoptosis in human esophageal cancer cell line Kyse510. Inhibition of oxidative stress by the antioxidant N-acetylcysteine blocked the induction of apoptosis by dioscin, indicating that ROS generation is the primary mechanism responsible for the proapoptotic activity of dioscin. Proteomic analysis and protein gel blotting further revealed peroxiredoxins 1 and 6 (PRDX 1 and 6), which are implicated in ROS metabolism and apoptosis, were associated with the anticancer effects of dioscin. Meanwhile, overexpression of PRDX 1 and 6 significantly blocked the elevated ROS and apoptosis induced by dioscin. In conclusion, we suggest that PRDX1 and PRDX6 are key targets in the process of dioscin-induced apoptosis that involves intracellular elevated ROS.

[1]  W. Bshara,et al.  Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature. , 2011, Cancer research.

[2]  Y. Jung,et al.  Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase , 2011, Cell Death and Differentiation.

[3]  X. Guan,et al.  Spatholobus suberectus inhibits cancer cell growth by inducing apoptosis and arresting cell cycle at G2/M checkpoint. , 2011, Journal of ethnopharmacology.

[4]  Yong-Man Kim,et al.  Peroxiredoxin 6 Overexpression Attenuates Cisplatin-Induced Apoptosis in Human Ovarian Cancer Cells , 2011, Cancer investigation.

[5]  Soo-Ki Kim,et al.  Involvement of oxidative stress in simvastatin-induced apoptosis of murine CT26 colon carcinoma cells. , 2010, Toxicology letters.

[6]  S. Fulda.  Exploiting mitochondrial apoptosis for the treatment of cancer. , 2010, Mitochondrion.

[7]  Seamus J. Martin,et al.  Mitochondrial fission/fusion dynamics and apoptosis. , 2010, Mitochondrion.

[8]  J. Dalton,et al.  Peroxiredoxin: a central player in immune modulation , 2010, Parasite immunology.

[9]  Sang-Gu Hwang,et al.  Phospholipase A2 Activity of Peroxiredoxin 6 Promotes Invasion and Metastasis of Lung Cancer Cells , 2010, Molecular Cancer Therapeutics.

[10]  Tak Yee Aw,et al.  Reactive oxygen species, cellular redox systems, and apoptosis. , 2010, Free radical biology & medicine.

[11]  H. Forman,et al.  Signaling functions of reactive oxygen species. , 2010, Biochemistry.

[12]  P. Storz,et al.  Reactive oxygen species in cancer , 2010, Free radical research.

[13]  A. Letai,et al.  Control of mitochondrial apoptosis by the Bcl-2 family , 2009, Journal of Cell Science.

[14]  M. Bennett,et al.  Role of Fas/Fas-L in Vascular Cell Apoptosis , 2009, Journal of cardiovascular pharmacology.

[15]  S. Baek,et al.  Up-Regulation of Peroxiredoxin 1 in Lung Cancer and Its Implication as a Prognostic and Therapeutic Target , 2008, Clinical Cancer Research.

[16]  陳中一.  Isoobtusilactone A Induces Cell Cycle Arrest and Apoptosis Through Reactive Oxygen Species/Apoptosis Signal-regulating Kinase 1 Signaling Pathway in Human Breast Cancer Cells , 2008 .

[17]  D. Kwong,et al.  Identification of alpha‐actinin 4 and 67 kDa laminin receptor as stage‐specific markers in esophageal cancer via proteomic approaches , 2007, Cancer.

[18]  G. Wondrak,et al.  Experimental therapeutics: targeting the redox Achilles heel of cancer. , 2007, Current opinion in investigational drugs.

[19]  S. Jana,et al.  Apoptosis: potential therapeutic targets for new drug discovery. , 2007, Current medicinal chemistry.

[20]  Clement Ip,et al.  Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex. , 2006, Cancer research.

[21]  Qing‐Yu He,et al.  Proteomic approach to study the cytotoxicity of dioscin (saponin) , 2006, Proteomics.

[22]  Woojin Jeong,et al.  2-Cys peroxiredoxin function in intracellular signal transduction: therapeutic implications , 2005, Trends in Molecular Medicine.

[23]  A. Fisher,et al.  Peroxiredoxin 6, a 1-Cys peroxiredoxin, functions in antioxidant defense and lung phospholipid metabolism. , 2005, Free radical biology & medicine.

[24]  P. Marrack,et al.  T cell apoptosis and reactive oxygen species. , 2003, The Journal of clinical investigation.

[25]  Xiuwen Han,et al.  Synthesis of monomethylated dioscin derivatives and their antitumor activities. , 2003, Carbohydrate research.

[26]  Yong Ju,et al.  Apoptosis induced by dioscin in Hela cells. , 2002, Biological & pharmaceutical bulletin.

[27]  S. de Jong,et al.  Fas receptor‐mediated apoptosis: a clinical application? , 2002, The Journal of pathology.

[28]  S. Rhee,et al.  Peroxiredoxin, a Novel Family of Peroxidases , 2001, IUBMB life.

[29]  F. Levi-Schaffer,et al.  Role of reactive oxygen species (ROS) in apoptosis induction , 2000, Apoptosis.

[30]  F. Sánchez-Jiménez,et al.  Role of reactive oxygen species in apoptosis: implications for cancer therapy. , 2000, The international journal of biochemistry & cell biology.

[31]  C. Nathan,et al.  Production of large amounts of hydrogen peroxide by human tumor cells. , 1991, Cancer research.

[32]  Peng Huang,et al.  Models of reactive oxygen species in cancer. , 2007, Drug discovery today. Disease models.

[33]  A. Evens,et al.  Oxidative stress and apoptosis: a new treatment paradigm in cancer. , 2006, Frontiers in bioscience : a journal and virtual library.