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New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin

Published:November 12, 2008DOI:https://doi.org/10.1016/j.ctrv.2008.09.005

      Summary

      Traditional Chinese medicines have been recently recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects of cancer chemotherapies however their healing mechanisms are still largely unknown. Scutellariabaicalensis is one of the most popular and multi-purpose herb used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections. Accumulating evidence demonstrate that Scutellaria also possesses potent anticancer activities. The bioactive components of Scutellaria have been confirmed to be flavones. The major constituents of Scutellaria baicalensis are Wogonin, Baicalein and Baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The antitumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-κB activity, to inhibit several genes important for regulation of the cell cycle, to suppress COX-2 gene expression and to prevent viral infections. The tumor-selectivity of Wogonin has recently been demonstrated to be due to its ability to differentially modulate the oxidation–reduction status of malignant vs. normal lymphocytic cells and to preferentially induce phospholipase Cγ1, a key enzyme involved in Ca2+ signaling, through H2O2 signaling in malignant lymphocytes. This review is aimed to summarize the research results obtained since the last 20 years and to highlight the recently discovered molecular mechanisms.

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      References

        • Rhoads C.P.
        Report on a cooperative study of nitrogen mustard (HN2) therapy of neoplastic disesase.
        Trans Assoc Am Physicians. 1947; 60: 110-111
      1. Boik J. Natural Compounds in Cancer Therapy, ISBN 0-9648280-1-4, Oregon Medical 2001.LLC.

        • Abelson P.H.
        Medicine from plants.
        Science. 1990; 247: 513
        • Newman D.J.
        • Cragg G.M.
        • Snader K.M.
        Natural products as sources of new drugs over the period 1981–2002.
        J Nat Prod. 2003; 66: 1022-1037
        • Yano H.
        • Mizoguchi A.
        • Fukuda K.
        • Haramaki M.
        • Ogasawara S.
        • Momosaki S.
        • et al.
        The herbal medicine sho-saiko-to inhibits proliferation of cancer cell lines by inducing apoptosis and arrest at the G0/G1 phase.
        Cancer Res. 1994; 54: 448-454
        • Motoo Y.
        • Sawabu N.
        Antitumor effects of saikosaponins, Baicalin and Baicalein on human hepatoma cell lines.
        Cancer Lett. 1994; 86: 91-95
        • Ikemoto S.
        • Sugimura K.
        • Yoshida N.
        • Yasumoto R.
        • Wada S.
        • Yamamoto K.
        • et al.
        Antitumor effects of Scutellariae radix and its components Baicalein, Baicalin and Wogonin on bladder cancer cell lines.
        Urology. 2000; 55: 951-955
        • Zhang D.Y.
        • Wu J.
        • Ye F.
        • Xue L.
        • Jiang S.
        • Yi J.
        • et al.
        Inhibition of cancer cell proliferation and prostaglandin E2 synthesis by Scutellaria baicalensis.
        Cancer Res. 2003; 63: 4037-4043
        • Yu J.
        • Liu H.
        • Lei J.
        • Tan W.
        • Hu X.
        • Zou G.
        Antitumor activity of chloroform fraction of Scutellaria barbata and its active constituents.
        Phytother Res. 2007; 21: 817-822
        • Middleton Jr, E.
        • Kandaswami C.
        • Theoharides T.C.
        The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.
        Pharmacol Rev. 2000; 52: 673-751
        • Havsteen B.H.
        The biochemistry and medical significance of the flavonoids.
        Pharmacol Ther. 2002; 96: 67-202
        • Gao Z.
        • Huang K.
        • Yang X.
        • Xu H.
        Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi.
        Biochim Biophys Acta. 1999; 1472: 643-650
        • Wang H.K.
        • Xia Y.
        • Yang Z.Y.
        • Natschke S.L.
        • Lee K.H.
        Recent advances in the discovery and development of flavonoids and their analogues as antitumor and anti-HIV agents.
        Adv Exp Med Biol. 1998; 439: 191-225
        • Wu J.A.
        • Attele A.S.
        • Zhang L.
        • Yuan C.S.
        Anti-HIV activity of medicinal herbs: usage and potential development.
        Am J Chin Med. 2001; 29: 69-81
        • Ma S.C.
        • Du J.
        • But P.P.
        • Deng X.L.
        • Zhang Y.W.
        • Ooi V.E.
        • et al.
        Anti-viral Chinese medicinal herbs against respiratory syncytial virus.
        J Ethnopharmacol. 2002; 79: 205-211
        • Huang R.L.
        • Chen C.C.
        • Huang H.L.
        • Chang C.G.
        • Chen C.F.
        • Chang C.
        • et al.
        Anti-hepatitis B virus effects of Wogonin isolated from Scutellaria baicalensis.
        Planta Med. 2000; 66: 694-698
        • Guo Q.
        • Zhao L.
        • You Q.
        • Yang Y.
        • Gu H.
        • Song G.
        • et al.
        Anti-hepatitis B virus activity of Wogonin in vitro and in vivo.
        Antiviral Res. 2007; 74: 16-24
        • Kimura Y.
        • Okuda H.
        • Ogita Z.
        Effects of flavonoids isolated from scutellaria radix on fibrinolytic system induced by trypsin in human umbilical vein endothelial cells.
        J Nat Prod. 1997; 60: 598-601
        • Huang Y.
        • Tsang S.Y.
        • Yao X.
        • Chen Z.Y.
        Biological properties of Baicalein in cardiovascular system.
        Curr Drug Targets Cardiovasc Haematol Disord. 2005; 5: 177-184
        • Chi Y.S.
        • Lim H.
        • Park H.
        • Kim H.P.
        Effects of Wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression.
        Biochem Pharmacol. 2003; 66: 1271-1278
        • Wang C.Z.
        • Mehendale S.R.
        • Yuan C.S.
        Commonly used antioxidant botanicals: active constituents and their potential role in cardiovascular illness.
        Am J Chin Med. 2007; 35: 543-558
        • Lee H.H.
        • Yang L.L.
        • Wang C.C.
        • Hu S.Y.
        • Chang S.F.
        • Lee Y.H.
        Differential effects of natural polyphenols on neuronal survival in primary cultured central neurons against glutamate- and glucose deprivation-induced neuronal death.
        Brain Res. 2003; 986: 103-113
        • Lee H.
        • Kim Y.O.
        • Kim H.
        • Kim S.Y.
        • Noh H.S.
        • Kang S.S.
        • et al.
        Flavonoid Wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia.
        FASEB J. 2003; 17: 1943-1944
        • Son D.
        • Lee P.
        • Lee J.
        • Kim H.
        • Kim S.Y.
        Neuroprotective effect of Wogonin in hippocampal slice culture exposed to oxygen and glucose deprivation.
        Eur J Pharmacol. 2004; 493: 99-102
        • Piao H.Z.
        • Jin S.A.
        • Chun H.S.
        • Lee J.C.
        • Kim W.K.
        Neuroprotective effect of Wogonin: potential roles of inflammatory cytokines.
        Arch Pharm Res. 2004; 27: 930-936
        • Cho J.
        • Lee H.K.
        Wogonin inhibits excitotoxic and oxidative neuronal damage in primary cultured rat cortical cells.
        Eur J Pharmacol. 2004; 485: 105-110
        • Cho J.
        • Lee H.K.
        Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion.
        Biol Pharm Bull. 2004; 27: 1561-1564
        • You K.M.
        • Jong H.G.
        • Kim H.P.
        Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from medicinal plants.
        Arch Pharm Res. 1999; 22: 18-24
        • Kim H.K.
        • Cheon B.S.
        • Kim Y.H.
        • Kim S.Y.
        • Kim H.P.
        Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264. 7 and their structure-activity relationships.
        Biochem Pharmacol. 1999; 58: 759-765
        • Kim H.
        • Kim Y.S.
        • Kim S.Y.
        • Suk K.
        The plant flavonoid Wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production.
        Neurosci Lett. 2001; 309: 67-71
        • Wakabayashi I.
        • Yasui K.
        Wogonin inhibits inducible prostaglandin E(2) production in macrophages.
        Eur J Pharmacol. 2000; 406: 477-481
        • Chen Y.C.
        • Shen S.C.
        • Chen L.G.
        • Lee T.J.
        • Yang L.L.
        Wogonin, Baicalin and Baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide.
        Biochem Pharmacol. 2001; 61: 1417-1427
        • Park B.K.
        • Heo M.Y.
        • Park H.
        • Kim H.P.
        Inhibition of TPA-induced cyclooxygenase-2 expression and skin inflammation in mice by Wogonin, a plant flavone from Scutellaria radix.
        Eur J Pharmacol. 2001; 425: 153-157
        • Shen S.C.
        • Lee W.R.
        • Lin H.Y.
        • Huang H.C.
        • Ko C.H.
        • Yang L.L.
        • et al.
        In vitro and in vivo inhibitory activities of rutin, Wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production.
        Eur J Pharmacol. 2002; 446: 187-194
        • Haranaka R.
        • Hasegawa R.
        • Nakagawa S.
        • Sakurai A.
        • Satomi N.
        • Haranaka K.
        Antitumor activity of combination therapy with traditional Chinese medicine and OK432 or MMC.
        J Biol Response Mod. 1988; 7: 77-90
        • Yamamoto S.
        • Oka H.
        • Kanno T.
        • Mizoguchi Y.
        • Kobayashi K.
        Controlled prospective trial to evaluate Syosakiko-to in preventing hepatocellular carcinoma in patients with cirrhosis of the liver.
        Gan To Kagaku Ryoho. 1989; 16: 1519-1524
        • Ma Z.
        • Otsuyama K.
        • Liu S.
        • Abroun S.
        • Ishikawa H.
        • Tsuyama N.
        • et al.
        Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells.
        Blood. 2005; 105: 3312-3318
        • Han J.
        • Ye M.
        • Xu M.
        • Sun J.
        • Wang B.
        • Guo D.
        Characterization of flavonoids in the traditional Chinese herbal medicine-Huangqin by liquid chromatography coupled with electrospray ionization mass spectrometry.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2007; 848: 355-362
        • Gao J.
        • Sanchez-Medina A.
        • Pendry B.A.
        • Hughes M.J.
        • Webb G.P.
        • Corcoran O.
        Validation of a HPLC method for flavonoid biomarkers in skullcap (Scutellaria) and its use to illustrate wide variability in the quality of commercial tinctures.
        J Pharm Pharm Sci. 2008; 11: 77-87
        • Wang H.Z.
        • Yu C.H.
        • Gao J.
        • Zhao G.R.
        Effects of processing and extracting methods on active components in radix Scutellariae by HPLC analysis.
        Zhongguo Zhong Yao Za Zhi. 2007; 32: 1637-1640
        • Chung H.
        • Jung Y.M.
        • Shin D.H.
        • Lee J.Y.
        • Oh M.Y.
        • Kim H.J.
        • et al.
        Anticancer effects of Wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts.
        Int J Cancer. 2008; 122: 816-822
        • Kuntz S.
        • Wenzel U.
        • Daniel H.
        Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines.
        Eur J Nutr. 1999; 38: 133-142
        • So F.V.
        • Guthrie N.
        • Chambers A.F.
        • Carroll K.K.
        Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen.
        Cancer Lett. 1997; 112: 127-133
        • Roy M.K.
        • Nakahara K.
        • Na T.V.
        • Trakoontivakorn G.
        • Takenaka M.
        • Isobe S.
        • et al.
        Baicalein, a flavonoid extracted from a methanolic extract of Oroxylum indicum inhibits proliferation of a cancer cell line in vitrovia induction of apoptosis.
        Pharmazie. 2007; 62: 149-153
        • Sonoda M.
        • Nishiyama T.
        • Matsukawa Y.
        • Moriyasu M.
        Cytotoxic activities of flavonoids from two Scutellaria plants in Chinese medicine.
        J Ethnopharmacol. 2004; 91: 65-68
        • Himeji M.
        • Ohtsuki T.
        • Fukazawa H.
        • Tanaka M.
        • Yazaki S.
        • Ui S.
        • et al.
        Difference of growth-inhibitory effect of Scutellaria baicalensis-producing flavonoid Wogonin among human cancer cells and normal diploid cell.
        Cancer Lett. 2007; 245: 269-274
        • Shieh D.E.
        • Cheng H.Y.
        • Yen M.H.
        • Chiang L.C.
        • Lin C.C.
        Baicalin-induced apoptosis is mediated by Bcl-2-dependent, but not p53-dependent, pathway in human leukemia cell lines.
        Am J Chin Med. 2006; 34: 245-261
        • Zhang H.W.
        • Yang Y.
        • Zhang K.
        • Qiang L.
        • Yang L.
        • Yang L.
        • et al.
        Wogonin induced differentiation and G1 phase arrest of human U-937 leukemia cells via PKCdelta phosphorylation.
        Eur J Pharmacol. 2008; 591: 7-12
        • Yu J.Q.
        • Liu H.B.
        • Tian D.Z.
        • Liu Y.W.
        • Lei J.C.
        • Zou G.L.
        Changes in mitochondrial membrane potential and reactive oxygen species during Wogonin-induced cell death in human hepatoma cells.
        Hepatol Res. 2007; 37: 68-76
        • Wang W.
        • Guo Q.
        • You Q.
        • Zhang K.
        • Yang Y.
        • Yu J.
        • et al.
        Involvement of Bax/Bcl-2 in Wogonin-induced apoptosis of human hepatoma cell line SMMC-7721.
        Anticancer Drugs. 2006; 17: 797-805
        • Wong B.C.
        • Wang W.P.
        • Cho C.H.
        • Fan X.M.
        • Lin M.C.
        • Kung H.F.
        • et al.
        12-Lipoxygenase inhibition induced apoptosis in human gastric cancer cells.
        Carcinogenesis. 2001; 22: 1349-1354
        • Leung H.W.
        • Yang W.H.
        • Lai M.Y.
        • Lin C.J.
        • Lee H.Z.
        Inhibition of 12-lipoxygenase during Baicalein-induced human lung nonsmall carcinoma H460 cell apoptosis.
        Food Chem Toxicol. 2007; 45: 403-411
        • Lee H.Z.
        • Leung H.W.
        • Lai M.Y.
        • Wu C.H.
        Baicalein-induced cell cycle arrest and apoptosis in human lung squamous carcinoma CH27 cells.
        Anticancer Res. 2005; 25: 959-964
        • Li Q.B.
        • You Y.
        • Chen Z.C.
        • Lü J.
        • Shao J.
        • Zou P.
        Role of Baicalein in the regulation of proliferation and apoptosis in human myeloma RPMI8226 cells.
        Chin Med J (Engl). 2006; 119: 948-952
        • Bonham M.
        • Posakony J.
        • Coleman I.
        • Montgomery B.
        • Simon J.
        • Nelson P.S.
        Characterization of chemical constituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitory activities toward prostate carcinoma.
        Clin Cancer Res. 2005; 11: 3905-3914
        • Chen S.
        • Ruan Q.
        • Bedner E.
        • Deptala A.
        • Wang X.
        • Hsieh T.C.
        • et al.
        Effects of the flavonoid Baicalin and its metabolite Baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines.
        Cell Prolif. 2001; 34: 293-304
        • Pidgeon G.P.
        • Kandouz M.
        • Meram A.
        • Honn K.V.
        Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells.
        Cancer Res. 2002; 62: 2721-2727
        • Chan F.L.
        • Choi H.L.
        • Chen Z.Y.
        • Chan P.S.
        • Huang Y.
        Induction of apoptosis in prostate cancer cell lines by a flavonoid, Baicalin.
        Cancer Lett. 2000; 160: 219-228
        • Lee J.H.
        • Li Y.C.
        • Ip S.W.
        • Hsu S.C.
        • Chang N.W.
        • Tang N.Y.
        • et al.
        The role of Ca2+ in Baicalein-induced apoptosis in human breast MDA-MB-231 cancer cells through mitochondria- and caspase-3-dependent pathway.
        Anticancer Res. 2008; 28: 1701-1711
        • Chow J.M.
        • Huang G.C.
        • Shen S.C.
        • Wu C.Y.
        • Lin C.W.
        • Chen Y.C.
        Differential apoptotic effect of Wogonin and nor-Wogonin via stimulation of ROS production in human leukemia cells.
        J Cell Biochem. 2008; 103: 1394-1404
        • Lee W.R.
        • Shen S.C.
        • Lin H.Y.
        • Hou W.C.
        • Yang L.L.
        • Chen Y.C.
        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.
        Biochem Pharmacol. 2002; 63: 225-236
        • Baumann S.
        • Fas S.C.
        • Giaisi M.
        • Müller W.W.
        • Merling A.
        • Gülow K.
        • et al.
        Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLC{gamma}1- and Ca2+-dependent apoptosis.
        Blood. 2008; 111: 2354-2363
        • Chang W.H.
        • Chen C.H.
        • Lu F.J.
        Different effects of Baicalein, Baicalin and Wogonin on mitochondrial function, glutathione content and cell cycle progression in human hepatoma cell lines.
        Planta Med. 2002; 68: 128-132
        • Chen Y.C.
        • Shen S.C.
        • Lee W.R.
        • Lin H.Y.
        • Ko C.H.
        • Shih C.M.
        • et al.
        Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1.
        Arch Toxicol. 2002; 76: 351-359
        • Lee D.H.
        • Kim C.
        • Zhang L.
        • Lee Y.J.
        Role of p53, PUMA, and Bax in Wogonin-induced apoptosis in human cancer cells.
        Biochem Pharmacol. 2008; 75: 2020-2033
        • Wang W.
        • Guo Q.L.
        • You Q.D.
        • Zhang K.
        • Yang Y.
        • Yu J.
        • et al.
        The anticancer activities of Wogonin in murine sarcoma S180 both in vitro and in vivo.
        Biol Pharm Bull. 2006; 29: 1132-1137
        • Lu N.
        • Gao Y.
        • Ling Y.
        • Chen Y.
        • Yang Y.
        • Gu H.Y.
        • et al.
        Wogonin suppresses tumor growth in vivo and VEGF-induced angiogenesis through inhibiting tyrosine phosphorylation of VEGFR2.
        Life Sci. 2008; 82: 956-963
        • Enomoto R.
        • Sugahara C.
        • Suzuki C.
        • Nagase I.
        • Takamura Y.
        • Yoshikawa A.
        • et al.
        Wogonin prevents glucocorticoid-induced thymocyte apoptosis without diminishing its anti-inflammatory action.
        J Pharmacol Sci. 2007; 104: 355-365
        • Kawai M.
        • Hirano T.
        • Higa S.
        • Arimitsu J.
        • Maruta M.
        • Kuwahara Y.
        • et al.
        Flavonoids and related compounds as anti-allergic substances.
        Allergol Int. 2007; 56: 113-123
        • Hausen B.M.
        Evaluation of the main contact allergens in propolis (1995 to 2005).
        Dermatitis. 2005; 16: 127-129
        • Schuler T.M.
        • Frosch P.J.
        Propolis-induced contact allergy.
        Hautarzt. 1988; 39: 139-142
        • Lee B.S.
        • Shim S.M.
        • Heo J.
        • Pae H.O.
        • Seo B.Y.
        • Han S.Y.
        • et al.
        Wogonin suppresses TARC expression induced by mite antigen via heme oxygenase 1 in human keratinocytes Suppressive effect of Wogonin on mite antigen-induced TARC expression.
        J Dermatol Sci. 2007; 46: 31-40
        • Taniguchi C.
        • Homma M.
        • Takano O.
        • Hirano T.
        • Oka K.
        • Aoyagi Y.
        • et al.
        Pharmacological effects of urinary products obtained after treatment with saiboku-to, a herbal medicine for bronchial asthma, on type IV allergic reaction.
        Planta Med. 2000; 66: 607-611
        • Curtin J.F.
        • Donovan M.
        • Cotter T.G.
        Regulation and measurement of oxidative stress in apoptosis.
        J Immunol Metohods. 2002; 265: 49-72
        • Storz P.
        Reactive oxygen species in tumor progression.
        Front Biosci. 2005; 10: 1881-1896
        • Rice-Evans C.A.
        • Miller N.J.
        • Paganga G.
        Structure-antioxidant activity relationships of flavonoids and phenlic acids.
        Free Radic Biol Med. 1996; 20: 933-956
        • Cao G.
        • Sofic E.
        • Prior R.L.
        Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships.
        Free Radic Biol Med. 1997; 22: 749-760
        • Valko M.
        • Rhodes C.J.
        • Moncol J.
        • Izakovic M.
        • Mazur M.
        Free radicals, metals and antioxidants in oxidative stress-induced cancer.
        Chem Biol Interact. 2006; 160: 1-40
        • Brown J.E.
        • Khodr H.
        • Hider R.C.
        • Rice-Evans C.A.
        Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties.
        Biochem. J. 1998; : 1173-1178
        • Morel I.
        • Lescoat G.
        • Cillard P.
        • Cillard J.
        Role of flavonoids and iron chelation in antioxidant action.
        Methods Enzymol. 1994; 234: 437-443
        • Williams R.J.
        • Spencer J.P.
        • Rice-Evans C.
        Flavonoids: antioxidants or signaling molecules?.
        Free Radic Biol Med. 2004; 36: 838-849
        • Kagan V.E.
        • Kuzmenko A.I.
        • Tyurina Y.Y.
        • Shvedova A.A.
        • Matsura T.
        • Yalowich J.C.
        Pro-oxidant and antioxidant mechanisms of etoposide in HL-60 cells: role of myeloperoxidase.
        Cancer Res. 2001; 61: 7777-7784
        • Modriansky M.
        • Tyurina Y.Y.
        • Tyurin V.A.
        • Matsura T.
        • Shvedova A.A.
        • Yalowich J.C.
        • et al.
        Anti-/pro-oxidant effects of phenolic compounds in cells: are colchicine metabolites chain-breaking antioxidants?.
        Toxicology. 2002; 177: 105-117
        • Miyoshi N.
        • Naniwa K.
        • Yamada T.
        • Osawa T.
        • Nakamura Y.
        Dietary flavonoid apigenin is a potential inducer of intracellular oxidative stress: the role in the interruptive apoptotic signal.
        Arch Biochem Biophys. 2007; 466: 274-282
        • Kachadourian R.
        • Leitner H.M.
        • Day B.J.
        Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: a role for glutathione depletion.
        Int J Oncol. 2007; 31: 161-168
        • Kachadourian R.
        • Day B.J.
        Flavonoid-induced glutathione depletion: potential implications for cancer treatment.
        Free Radic Biol Med. 2006; 41: 65-76
        • Pantano C.
        • Reynaert N.L.
        • van der Vliet A.
        • Janssen-Heininger Y.M.
        Redox-sensitive kinases of the nuclear factor-kappaB signaling pathway.
        Antioxid Redox Signal. 2006; 8: 1791-1806
        • Nakano H.
        • Nakajima A.
        • Sakon-Komazawa S.
        • Piao J.H.
        • Xue X.
        • Okumura K.
        Reactive oxygen species mediate crosstalk between NF-kappaB and JNK.
        Cell Death Differ. 2006; 13: 730-737
        • Jost P.J.
        • Ruland J.
        Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications.
        Blood. 2007; 109: 2700-2707
        • Suh J.
        • Rabson A.B.
        NF-kappaB activation in human prostate cancer: important mediator or epiphenomenon?.
        J Cell Biochem. 2004; 91: 100-117
        • François S.
        • El Benna J.
        • Dang P.M.
        • Pedruzzi E.
        • Gougerot-Pocidalo M.A.
        • Elbim C.
        Inhibition of neutrophil apoptosis by TLR agonists in whole blood: involvement of the phosphoinositide 3-kinase/Akt and NF-kappaB signaling pathways, leading to increased levels of Mcl-1, A1, and phosphorylated Bad.
        J Immunol. 2005; 174: 3633-3642
        • Szatrowski T.P.
        • Nathan C.F.
        Production of large amounts of hydrogen peroxide by human tumor cells.
        Cancer Res. 1991; 51: 794-798
        • Toyokuni S.
        • Okamoto K.
        • Yodoi J.
        • Hiai H.
        Persistent oxidative stress in cancer.
        FEBS Lett. 1995; 358: 1-3
        • Portakal O.
        • Ozkaya O.
        • Erden Inal M.
        • Bozan B.
        • Kosan M.
        • Sayek I.
        (2000) Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients.
        Clin Biochem. 2000; 33: 279-284
        • Fas S.C.
        • Baumann S.
        • Zhu J.Y.
        • Giaisi M.
        • Treiber M.K.
        • Mahlknecht U.
        • et al.
        Wogonin sensitizes resistant malignant cells to TNFalpha- and TRAIL-induced apoptosis.
        Blood. 2006; 108: 3700-3706
        • Schwartz G.K.
        • Shah M.A.
        Targeting the cell cycle: a new approach to cancer therapy.
        J Clin Oncol. 2005; 23: 9408-9421
        • Shapiro G.I.
        Cyclin-dependent kinase pathways as targets for cancer treatment.
        J Clin Oncol. 2006; 24: 1770-1783
        • Blagosklonny M.V.
        • Pardee A.B.
        The restriction point of the cell cycle.
        Cell cycle. 2002; 1: 103-110
        • Roy P.G.
        • Thompson A.M.
        Cyclin D1 and breast cancer.
        Breast. 2006; 15: 718-727
        • Hideshima T.
        • Bergsagel P.L.
        • Kuehl W.M.
        • Anderson K.C.
        Advances in biology of multiple myeloma: clinical applications.
        Blood. 2004; 104: 607-618
        • Hinz M.
        • Krappmann D.
        • Eichten A.
        • Heder A.
        • Scheidereit C.
        • Strauss M.
        NF-kappaB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
        Mol Cell Biol. 1999; 19: 2690-2698
        • Guttridge D.C.
        • Albanese C.
        • Reuther J.Y.
        • Pestell R.G.
        • Baldwin Jr, A.S.
        NF-κB controls cell growth ad differentiation through the transcriptional regulation of cyclin D1.
        Mol Cell Biol. 1999; 19: 5785-5799
        • Joyce D.
        • Albanese C.
        • Steer J.
        • Fu M.
        • Bouzahzah B.
        • Pestell R.G.
        NF-kappaB and cell-cycle regulation: the cyclin connection.
        Cytokine Growth Factor Rev. 2001; 12: 73-90
        • Galluzzi L.
        • Larochette N.
        • Zamzami N.
        • Kroemer G.
        Mitochondria as therapeutic targets for cancer chemotherapy.
        Oncogene. 2006; 25: 4812-4830
        • Debatin K.M.
        • Krammer P.H.
        Death receptors in chemotherapy and cancer.
        Oncogene. 2004; 23: 2950-2966
        • Budd R.C.
        • Yeh W.C.
        • Tschopp J.
        CFLIP regulation of lymphocyte activation and development.
        Nat Rev Immunol. 2006; 6: 196-204
        • Krammer P.H.
        • Arnold R.
        • Lavrik I.N.
        Life and death in peripheral T-cells.
        Nat Rev Immunol. 2007; 7: 532-542
        • Barnhart B.C.
        • Alappat E.C.
        • Peter M.E.
        The CD95 type I/type II model.
        Semin Immunol. 2003; 15: 185-193
        • Beg A.A.
        • Baltimore D.
        An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.
        Science. 1996; 274: 782-784
        • Van Antwerp D.J.
        • Martin S.J.
        • Kafri T.
        • Green D.R.
        • Verma I.M.
        Suppression of TNF-alpha-induced apoptosis by NF-kappaB.
        Science. 1996; 274: 787-789
        • Wang C.Y.
        • Mayo M.W.
        • ASJr Baldwin.
        TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB.
        Science. 1996; 274: 784-787
        • Gulow K.
        • Kaminski M.
        • Darvas K.
        • Suss D.
        • Li-Weber M.
        • Krammer P.H.
        HIV-1 trans-activator of transcription substitutes for oxidative signaling in activation-induced T-cell death.
        J Immunol. 2005; 174: 5249-5260
        • Kaminski M.
        • Kießling M.
        • Suss D.
        • Krammer P.H.
        • Gulow G.
        Novel role for mitochondria: protein kinase c theta dependent oxidative signaling organelles in activation induced T-cell death.
        Mol Cell Biol. 2007; 27: 3625-3639
        • Akaishi T.
        • Nakazawa K.
        • Sato K.
        • Saito H.
        • Ohno Y.
        • Ito Y.
        Hydrogen peroxide modulates whole cell Ca2+ currents through L-type channels in cultured rat dentate granule cells.
        Neurosci Lett. 2004; 356: 25-28
        • Redondo P.C.
        • Salido G.M.
        • Rosado J.A.
        • Pariente J.A.
        Effect of hydrogen peroxide on Ca2+ mobilization in human platelets through sulphydryl oxidation dependent and independent mechanisms.
        Biochem Pharmacol. 2004; 67: 491-502
        • Hong J.H.
        • Moon S.J.
        • Byun H.M.
        • Kim M.S.
        • Jo H.
        • Bae Y.S.
        • et al.
        Critical role of phospholipase Cgamma1 in the generation of H2O2-evoked [Ca2+]i oscillations in cultured rat cortical astrocytes.
        J Biol Chem. 2006; 281: 13057-13067
        • Rizzuto R.
        • Pinton P.
        • Carrington W.
        • Fay F.S.
        • Fogarty K.E.
        • Lifshitz L.M.
        • et al.
        Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses.
        Science. 1998; 280: 1763-1766
        • Csordas G.
        • Thomas A.P.
        • Hajnoczky G.
        Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria.
        EMBO J. 1999; 18: 96-108
        • Montero M.
        • Lobatón C.D.
        • Hernández-Sanmiguel E.
        • Santodomingo J.
        • Vay L.
        • Moreno A.
        • et al.
        Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids.
        Biochem J. 2004; 384: 19-24
        • Wang H.G.
        • Pathan N.
        • Ethell I.M.
        • Krajewski S.
        • Yamaguchi Y.
        • Shibasaki F.
        • et al.
        Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.
        Science. 1999; 284: 339-343
        • Springer J.E.
        • Azbill R.D.
        • Nottingham S.A.
        • Kennedy S.E.
        Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury.
        J Neurosci. 2000; 20: 7246-7251
        • Datta S.R.
        • Ranger A.M.
        • Lin M.Z.
        • Sturgill J.F.
        • Ma Y.C.
        • Cowan C.W.
        • et al.
        Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.
        Dev Cell. 2002; 3: 631-643
        • Kotturi M.F.
        • Carlow D.A.
        • Lee J.C.
        • Ziltener H.J.
        • Jefferies W.A.
        Identification and functional characterization of voltage-dependent calcium channels in T lymphocytes.
        J Biol Chem. 2003; 278: 46949-46960
        • Badou A.
        • Basavappa S.
        • Desai R.
        • Peng Y.Q.
        • Matza D.
        • Mehal W.Z.
        • et al.
        Requirement of voltage-gated calcium channel beta4 subunit for T lymphocyte functions.
        Science. 2005; 307: 117-121
        • Coussens L.M.
        • Werb Z.
        Inflammation and cancer.
        Nature. 2002; 420: 860-867
        • Balkwill F.
        • Charles K.A.
        • Mantovani A.
        Smoldering and polarized inflammation in the initiation and promotion of malignant disease.
        Cancer Cell. 2005; 7: 211-217
        • Lim H.
        • Park H.
        • Kim H.P.
        Inhibition of contact dermatitis in animal models and suppression of proinflammatory gene expression by topically applied flavonoid, Wogonin.
        Arch Pharm Res. 2004; 27: 442-448
        • Lin C.C.
        • Shieh D.E.
        The anti-inflammatory activity of Scutellaria rivularis extracts and its active components, Baicalin, Baicalein and Wogonin.
        Am J Chin Med. 1996; 24: 31-36
        • Van Dien M.
        • Takahashi K.
        • Mu M.M.
        • Koide N.
        • Sugiyama T.
        • Mori I.
        • et al.
        Protective effect of Wogonin on endotoxin-induced lethal shock in D-galactosamine-sensitized mice.
        Microbiol Immunol. 2001; 45: 751-756
        • Hong T.
        • Jin G.B.
        • Cho S.
        • Cyong J.C.
        Evaluation of the anti-inflammatory effect of Baicalein on dextran sulfate sodium-induced colitis in mice.
        Planta Med. 2002; 68: 268-271
        • Fukumura D.
        • Kashiwagi S.
        • Jain R.K.
        The role of nitric oxide in tumor progression.
        Nature Reviews Cancer. 2006; 6: 521-534
        • Hussain S.P.
        • Hofseth L.J.
        • Harris C.C.
        Radical causes of cancer.
        Nat Rev Cancer. 2003; 3: 276-285
        • Chen C.J.
        • Raung S.L.
        • Liao S.L.
        • Chen S.Y.
        Inhibition of inducible nitric oxide synthase expression by Baicalein in endotoxin/cytokine-stimulated microglia.
        Biochem Pharmacol. 2004; 67: 957-965
        • Chen T.J.
        • Shen S.C.
        • Lin H.Y.
        • Chien L.L.
        • Chen Y.C.
        Lipopolysaccharide enhancement of 12-o-tetradecanoylphorbol 13-acetate-mediated transformation in rat glioma C6, accompanied by induction of inducible nitric oxide synthase.
        Toxicol Lett. 2004; 147: 1-3
        • Lo Y.C.
        • Lin Y.L.
        • Yu K.L.
        • Lai Y.H.
        • Wu Y.C.
        • Ann L.M.
        • et al.
        San-Huang-Xie-Xin-Tang attenuates inflammatory responses in lipopolysaccharide-exposed rat lungs.
        J Ethnopharmacol. 2005; 101: 68-74
        • Cheng P.Y.
        • Lee Y.M.
        • Wu Y.S.
        • Chang T.W.
        • Jin J.S.
        • Yen M.H.
        Protective effect of Baicalein against endotoxic shock in rats in vivo and in vitro.
        Biochem Pharmacol. 2007; 73: 793-804
        • Shih Y.T.
        • Wu D.C.
        • Liu C.M.
        • Yang Y.C.
        • Chen I.J.
        • Lo Y.C.
        San-Huang-Xie-Xin-Tang inhibits Helicobacter pylori-induced inflammation in human gastric epithelial AGS cells.
        J Ethnopharmacol. 2007; 112: 537-544
        • Park S.W.
        • Lee C.H.
        • Kim Y.S.
        • Kang S.S.
        • Jeon S.J.
        • Son K.H.
        • et al.
        Protective effect of Baicalin against carbon tetrachloride-induced acute hepatic injury in mice.
        J Pharmacol Sci. 2008; 106: 136-143
        • Shen S.C.
        • Lin C.W.
        • Lee H.M.
        • Chien L.L.
        • Chen Y.C.
        Lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate induction of migration and invasion of glioma cells in vitro and in vivo: differential inhibitory effects of flavonoids.
        Neuroscience. 2006; 140: 477-489
        • Hull M.A.
        • Ko S.C.
        • Hawcroft G.
        Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer?.
        Mol Cancer Ther. 2004; 3: 1031-1039
        • Subbaramaiah K.
        • Dannenberg A.J.
        Cyclooxygenase 2: a molecular target for cancer revention and treatment.
        Trends Pharmacol Sci. 2003; 24: 96-102
        • Vane J.R.
        • Bakhle Y.S.
        • Botting R.M.
        Cyclooxygenases 1 and 2.
        Annu Rev Pharmacol Toxicol. 1998; 38: 97-120
        • Castellone M.D.
        • Teramoto H.
        • Gutkind J.S.
        Cyclooxygenase-2 and colorectal cancer chemoprevention: the beta-catenin connection.
        Cancer Res. 2006; 66: 11085-11088
        • Torrance C.J.
        • Jackson P.E.
        • Montgomery E.
        • Kinzler K.W.
        • Vogelstein B.
        • Wissner A.
        • et al.
        Combinatorial chemoprevention of intestinal neoplasia.
        Nat Med. 2000; 6: 1024-1028
        • Brown J.R.
        • DuBois R.N.
        COX-2: a molecular target for colorectal cancer prevention.
        J Clin Oncol. 2005; 23: 2840-2855
      2. Chen LG, Hung LY, Tsai KW, Pan YS, Tsai YD, Li YZ, Liu YW. Wogonin, a bioactive flavonoid in herbal tea, inhibits inflammatory cyclooxygenase-2 gene expression in human lung epithelial cancer cells. Mol Nutr Food Res. 2008 May 21. [Epub ahead of print].

        • Li B.Q.
        • Fu T.
        • Gong W.H.
        • Dunlop N.
        • Kung H.
        • Yan Y.
        • et al.
        The flavonoid Baicalin exhibits anti-inflammatory activity by binding to chemokines.
        Immunopharmacology. 2000; 49: 295-306
        • zur Hausen H.
        Papillomaviruses and cancer: from basic studies to clinical application.
        Nature Reviews Cancer. 2002; 2: 342-350
        • Young L.S.
        • Rickinson A.B.
        Epstein-Barr virus: 40 years on.
        Nat Rev Cancer. 2004; 4: 757-768
        • Kensler T.W.
        • Qian G.
        • Chen J.
        Translational strategies for cancer prevention in liver.
        Nat Rev Cancer. 2003; 3: 321-329
        • Farazi Paraskevi.A.
        • PA De.Pinho.R.A.
        Hepatocellular carcinoma pathogenesis: from genes to environment.
        Nat Rev Cancer. 2006; 6: 674-687
        • Matsuoka M.
        • Jeang K.
        Human T-cell leukemia virus type 1 (HTLV-1) infectivity and cellular transformation.
        Nat Rev Cancer. 2007; 7: 270-280
        • Monini P.
        • Sgadari C.
        • Toschi E.
        • Giovanni Barillari G.
        • Ensoli B.
        Antitumor effects of antiretroviral therapy.
        Nat Rev Cancer. 2004; 4: 861-875
        • Nagai T.
        • Miyaichi Y.
        • Tomimori T.
        • Suzuki Y.
        • Yamada H.
        Inhibition of influenza virus sialidase and anti-influenza virus activity by plant flavonoids.
        Chem Pharm Bull (Tokyo). 1990; 38: 1329-1332
        • Li Y.
        • Ooi L.S.
        • Wang H.
        • But P.P.
        • Ooi V.E.
        Anti-viral activities of medicinal herbs traditionally used in Southern Mainland China.
        Phytother Res. 2004; 18: 718-722
        • Nunnari G.
        • Smith J.A.
        • Daniel R.
        HIV-1 Tat and AIDS-associated cancer: targeting the cellular anticancer barrier?.
        J Exp Clin Cancer Res. 2008; 27: 3
        • Baylor N.W.
        • Fu T.
        • Yan Y.D.
        • Ruscetti F.W.
        Inhibition of human T-cell leukemia virus by the plant flavonoid Baicalin (7-glucuronic acid, 5, 6-dihydroxyflavone).
        J Infect Dis. 1992 Mar; 165: 433-437
        • Ono K.
        • Nakane H.
        • Fukushima M.
        • Chermann J.C.
        • Barré-Sinoussi F.
        Inhibition of reverse transcriptase activity by a flavonoid compound, 5, 6, 7-trihydroxyflavone.
        Biochem Biophys Res Commun. 1989; 160: 982-987
        • Tang X.
        • Chen H.
        • Zhang X.
        Inhibition of human immunodeficiency virus reverse transcriptase by Chinese medicines in vitro.
        Proc Chin Acad Med Sci Peking Union Med Coll. 1990; 5: 140-144
        • Li B.Q.
        • Fu T.
        • Yan Y.D.
        • Baylor N.W.
        • Ruscetti F.W.
        • Kung H.F.
        Inhibition of HIV infection by Baicalin–a flavonoid compound purified from Chinese herbal medicine.
        Cell Mol Biol Res. 1993; 39: 119-124
        • Kitamura K.
        • Honda M.
        • Yoshizaki H.
        • Yamamoto S.
        • Nakane H.
        • Fukushima M.
        • et al.
        Baicalin, an inhibitor of HIV-1 production in vitro.
        Antiviral Res. 1998; 37: 131-140
        • Li B.Q.
        • Fu T.
        • Dongyan Y.
        • Mikovits J.A.
        • Ruscetti F.W.
        • Wang J.M.
        Flavonoid Baicalin inhibits HIV-1 infection at the level of viral entry.
        Biochem Biophys Res Commun. 2000; 276: 534-538
        • De Clercq E.
        Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection.
        Med Res Rev. 2000; 20: 323-349
        • Hussain S.P.
        • Schwank J.
        • Staib F.
        • Wang X.W.
        • Harris C.C.
        TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer.
        Oncogene. 2007; 26: 2166-2176
        • Romero M.R.
        • Efferth T.
        • Serrano M.A.
        • Castaño B.
        • Macias R.I.
        • Briz O.
        • et al.
        Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an “in vitro” replicative system.
        Antiviral Res. 2005; 68: 75-83
        • Tang Z.M.
        • Peng M.
        • Zhan C.J.
        Screening 20 Chinese herbs often used for clearing heat and dissipating toxin with nude mice model of hepatitis C viral infection.
        Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003; 23: 447-448
        • Kutok J.L.
        • Wang F.
        Spectrum of Epstein-Barr virus-associated diseases.
        Annu Rev Pathol. 2006; 1: 375-404
        • Konoshima T.
        • Kokumai M.
        • Kozuka M.
        • Iinuma M.
        • Mizuno M.
        • Tanaka T.
        • et al.
        Studies on inhibitors of skin tumor promotion.
        XI. Inhibitory effects of flavonoids from Scutellaria baicalensis on Epstein-Barr virus activation and their antitumor-promoting activities. Chem Pharm Bull (Tokyo). 1992; 40: 531-533
        • Wang H.W.
        • Lin C.P.
        • Chiu J.H.
        • Chow K.C.
        • Kuo K.T.
        • Lin C.S.
        • et al.
        Reversal of inflammation-associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by Wogonin and chrysin.
        Int J Cancer. 2007; 120: 2019-2027
        • Lee S.J.
        • Yoon J.H.
        • Song K.S.
        Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells.
        Biochem Pharmacol. 2007; 74: 215-225
        • Kim J.H.
        • Lee E.O.
        • Lee H.J.
        • Ku J.S.
        • Lee M.H.
        • Yang D.C.
        • et al.
        Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells.
        Ann N Y Acad Sci. 2006; 1090: 147-160