Wogonin Induces Apoptosis by Activation of ERK and p38 MAPKs Signaling Pathways and Generation of Reactive Oxygen Species in Human Breast Cancer Cells

다국어 초록 (Multilingual Abstract)

Wogonin is a one of the bioactive compounds of Scutellaria baicalensi Georgi which has been shown to have antiinflammatory, anticancer, antiviral and neuroprotective effects. However, the underlying mechanisms by which wogonin induces apoptosis in cancer cells still remain speculative. Here we investigated the potential activation of MAPKs and generation of reactive oxygen species (ROS) by wogonin on MCF-7 human breast cancer cells. These results showed that wogonin induced mitochondria and death-receptor-mediated apoptotic cell death, which was characterized by activation of several caspases, induction of PARP cleavage, change of antiapoptotic/pro-apoptotic Bcl-2 family member ratios and cleavage of Bid. We also found that generation of ROS was an important mediator in wogonin-induced apoptosis. Further investigation re-vealed that wogonin activated ERK and p38 MAPKs, which was inhibited by N-acetyl cysteine (NAC), a ROS scavenger, indicating that wogonin-induced ROS are associated with MAPKs activation. These data demonstrate that wogonin may be a novel anticancer agent for treatment of breast cancer

참고문헌 (Reference)

1 Chen, L.G., "Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells" 52 : 1349-1357, 2008

2 Enomoto, R., "Wogonin prevents immunosuppressive action but not anti-inflammatory effect induced by glucocorticoid" 1095 : 412-417, 2007

3 Lee, W.R., "Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)- dependent endonuclease" 63 : 225-236, 2002

4 Tai, M.C., "Therapeutic potential of wogonin: a naturally occurring flavonoid" 11 : 141-150, 2005

5 Tibbles, L.A., "The stress-activated protein kinase pathways" 55 : 1230-1254, 1999

6 Kim, H., "The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production" 309 : 67-71, 2001

7 Hengartner, M.O., "The biochemistry of apoptosis" 407 : 770-776, 2000

8 Wang, W., "The Anticancer Activities of Wogonin in Murine Sarcoma S180 both in vitro and in vivo" 29 : 1132-1137, 2006

9 Ghobrial, I.M., "Targeting apoptosis pathways in cancer therapy" 55 : 178-194, 2005

10 Davis, R.J., "Signal transduction by the JNK Group of MAP kinases" 103 : 239-252, 2000

11 Takeda, K., "Roles of MAPKKK ASK1 in stress-induced cell death" 28 : 23-29, 2003

12 Simon, H.U., "Role of reactive oxygen species(ROS)in apoptosis induction" 5 : 415-418, 2000

13 Wang, X., "Requirement for ERK activation in cisplatin-induced apoptosis" 275 : 39435-39443, 2000

14 Kamata, H., "Redox regulation of cellular signalling" 11 : 1-14, 1999

15 Ueda, S., "Redox control of cell death" 4 : 405-414, 2002

16 Schumacker, P.T., "Reactive oxygen species in cancer cells: live by the sword, die by the sword" 10 : 175-176, 2006

17 Benhar, M., "ROS, stress-activated kinases and stress signaling in cancer" 3 : 420-425, 2002

18 Arkin, M., "Protein-protein interactions and cancer: small molecules going in for the kill" 9 : 317-324, 2005

19 Fresco, P., "New insights on the anticancer properties of dietary polyphenols" 26 : 747-766, 2006

20 Lin, K.L., "Naphtho[1,2-b]furan-4,5-dione induces apoptosis and S-phase arrest of MDA-MB-231 cells through JNK and ERK signaling activation" 24 : 61-70, 2009

21 Wada, T., "Mitogen-activated protein kinases in apoptosis regulation" 23 : 2838-2849, 2004

22 Johnson, G.L., "Mitogen-activated protein kinase pathways mediated by ERK,JNK,and p38 protein kinases" 298 : 1911-1912, 2002

23 Shen, H.-M., "JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species" 40 : 928-939, 2006

24 Wang, W., "Involvement of bax/bcl-2 in wogonin-induced apoptosis of human hepatoma cell line SMMC-7721" 17 : 797-805, 2006

25 Liu, Z.L., "Induction of apoptosis in human lung fibroblasts and peripheral lymphocytes in vitro by Shosaiko-to derived phenolic metabolites" 25 : 37-41, 2002

26 Lee, H., "Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia" 17 : 1943-1944, 2003

27 Chi, Y.S., "Effects of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression" 66 : 1271-1278, 2003

28 Ramos, S., "Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention" 18 : 427-442, 2007

29 Khosravi-Far, R., "Death receptor signals to mitochondria" 3 : 1051-1057, 2004

30 Jemal, A., "Cancer statistics, 2009" 29 : 225-249, 2009

31 Strasser, A., "Apoptosis signaling" 69 : 217-245, 2000

32 Annunziato, L., "Apoptosis induced in neuronal cells by oxidative stress: role played by caspases and intracellular calcium ions" 139 : 125-133, 2003

33 Kumar, D., "Apoptosis and oxidants in the heart" 142 : 288-297, 2003

34 Ma, S.C., "Antiviral Chinese medicinal herbs against respiratory syncytial virus" 79 : 205-211, 2002

35 Ikemoto, S., "Antitumor effects of Scutellariae radix and its components baicalein, baicalin, and wogonin on bladder cancer cell lines" 55 : 951-955, 2000

36 Huang, W.H., "Antioxidative and anti-inflammatory activities of polyhydroxyflavonoids of Scutellaria baicalensis GEORGI" 70 : 2371-2380, 2006

37 Chung, H., "Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts" 122 : 816-822, 2008

38 Yoshiike, Y., "Amyloid oligomer conformation in a group of natively folded proteins" 3 : 3235-, 2008

39 Hye-Young Shim, "Acacetin-induced Apoptosis of Human Breast Cancer MCF-7 Cells Involves Caspase Cascade, Mitochondria-mediated Death Signaling and SAPK/JNK1/2-c-Jun Activation" 한국분자세포생물학회 24 (24): 95-104, 2007