Eupafolin, a flavonoid isolated from Artemisia princeps, induced apoptosis in human cervical adenocarcinoma HeLa cells

Department of Biomedical Science, College of Medical Science, Kyung-Hee University, Seoul, South Korea.
Molecular Nutrition & Food Research (Impact Factor: 4.6). 09/2010; 54(9):1318-28. DOI: 10.1002/mnfr.200900305
Source: PubMed


Although eupafolin, a flavone found in Artemisia princeps Pampanini, has been shown to inhibit the growth of several human cancer cells, its mode of action is poorly understood. In this study, we investigated the pro-apoptotic activities of eupafolin in human cervical carcinoma HeLa cells. It was found that eupafolin induced apoptosis in a dose-dependent manner, as evidenced by DNA fragmentation and the accumulation of positive cells for annexin V. In addition, eupafolin triggered the activations of caspases-3, -6, -7, -8, and -9 and the cleavages of their substrates, such as, poly (ADP-ribose) polymerase and lamin A/C. Furthermore, treatment with eupafolin resulted in a loss of mitochondrial membrane potential (DeltaPsi(m)), increased the release of cytochrome c to the cytosol, and altered the expression levels of B-cell lymphoma 2 (Bcl-2) family proteins. Interestingly, caspase-8, an initiator caspase, was activated after the loss of DeltaPsi(m) and the activations of caspases-3 and -9. Moreover, treatment with z-DEVD-fmk (a specific caspase-3 inhibitor) and the overexpression of Bcl-2 prevented eupafolin-stimulated caspase-8 activation. Altogether, these results suggest that the eupafolin-induced apoptosis in HeLa cells is mediated by caspase-dependent pathways, involving caspases-3, -9, and -8, which are initiated by the Bcl-2-dependent loss of DeltaPsi(m).

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    • "Sajabal induces apoptosis via mitochondrial pathway in human cervical cancer HeLa cells (Ju et al., 2012) and Artemisia leaf extract also induces apoptosis in human endometriotic cells through regulation of the p38 and NFκB pathways (Kim et al., 2013). Its flavonoid components, such as, eupatilin, jaceosidin, and eupafolin, induce G2/M cell cycle arrest and apoptosis via the caspase-and mitochondrial-dependent pathway and the inactivation of NF-κB pathways in human endometrial and cervical cancer cells (Cho et al., 2011; Chung et al., 2010; Lee et al., 2013). However, no report has been issued on the detailed in vivo and in vitro biological efficacies and involved the underlying molecular mechanism of EAPP in human colon cancer. "
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    ABSTRACT: Chronic inflammation is an underlying risk factor of colon cancer, and NF-κB plays a critical role in the development of inflammation-associated colon cancer in an AOM/DSS mouse model. The aim of this study was to determine whether the standardized ethanol extract obtained from the aerial parts of Artemisia princeps Pampanini cv. Sajabal (EAPP) is effective at preventing inflammation-associated colon cancer, and if so, to identify the signaling pathways involved. In the present study, protective efficacy of EAPP on tumor formation and the infiltrations of monocytes and macrophages in colons of an AOM/DSS mouse model were evaluated. It was found that colitis and tumor burdens showed statistically meaningful improvements after EAPP administration. Furthermore, these improvements were accompanied by a reduction in NF-κB activity and in the levels of NF-κB-dependent pro-survival proteins, that is, survivin, cFLIP, XIAP, and Bcl-2. In vitro, EAPP significantly reduced NF-κB activation and the levels of IL-1β and IL-8 mRNA and pro-survival proteins in HT-29 and HCT-116 colon cancer cells. Furthermore, EAPP caused caspase-dependent apoptosis. Based on these results, the authors suggest EAPP suppresses inflammatory responses and induces apoptosis partly via NF-κB inactivation, and that EAPP could be useful for the prevention of colitis-associated tumorigenesis.
    Full-text · Article · Nov 2014 · Food and Chemical Toxicology
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    • "Eupafolin isolated from methanol extracts of P. nodiflora has long been used in traditional Chinese medicine to treat inflammatory diseases . Antioxidant and anti-inflammatory activities were thought to be responsible for the beneficial effects (Chung et al., 2010). The putative functional groups of eupafolin, a benzene ring and the adjacent methoxy-hydroxyl groups (Fig. 1), serve as a potent inhibitor of Nox activity (Mladenka et al., 2010) Interestingly, pretreatment with APO (a specific inhibitor of Nox2) and NAC caused a significant suppression of LPS-induced COX-2 expression and PGE2 production. "
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    ABSTRACT: Eupafolin, a major active component found in the methanol extracts of Phyla nodiflora, has been used to treat inflammation of skin. We examined its effects on cyclooxygenase-2 (COX-2) expression in LPS-treated human dermal fibroblasts. Lipopolysaccharide (LPS) significantly increased prostaglandin-E2 (PGE2) production associated with increased COX-2 expression in Hs68 cells. This effect was blocked by eupafolin, TLR-4 antibody, antioxidants (APO and NAC), as well as inhibitors, including U0126 (ERK1/2), SB202190 (p38), SP600125 (JNK1/2), and Tanshinone IIA (AP-1). In gene regulation level, qPCR and promoter assays revealed that COX-2 expression was attenuated by eupafolin. In addition, eupafolin also ameliorated LPS-induced p47 phox activation, decreased reactive oxygen species (ROS) generation, and NADPH oxidase (Nox) activity. Moreover, pretreatment with eupafolin and APO led to reduced LPS-induced phosphorylation of ERK1/2, JNK, and p38. Further, eupafolin attenuated LPS-induced increase in AP-1 transcription factor binding activity as well as the increase in the phosphorylation of c-jun and c-fos. In vivo studies have shown that in dermal fibroblasts of LPS treated mice, eupafolin exerted anti-inflammation effects by decreasing COX-2 protein levels. Our results reveal a novel mechanism for anti-inflammatory and anti-oxidative effects of eupafolin that involved inhibition of LPS-induced ROS generation, suppression of MAPKs phosphorylation, diminished DNA binding activity of AP-1 and attenuated COX-2 expression leading to reduced production of prostaglandin E2 (PGE2). Our results demonstrate that eupafolin may be used to treat inflammatory responses associated with dermatologic diseases.
    Full-text · Article · Jun 2014 · Toxicology and Applied Pharmacology
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    • "Da-Huan-Hun, is a Chinese folk medicine in Taiwan, commonly used to alleviate pain, fever, inflammation, and injuries [8–10]. Its bioactive compounds include coumarin, bufadienolides, flavonoids (quercetin, kaempferol, teolin, quercitrin, and eupafolin), and glycosidic derivatives of eupafolin demonstrating antioxidant, anti-inflammatory, and/or antiproliferative activities [11–13]. K. gracilis leaf extract with ferulic acid, quercetin, and kaempferol shows moderately antiviral activity against CoxA16 and EV71 in vitro and in vivo [14]. "
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    ABSTRACT: Enterovirus 71 (EV71) and coxsackievirus A16 (CoxA16) are main pathogens of hand-foot-and-mouth disease, occasionally causing aseptic meningitis and encephalitis in tropical and subtropical regions. Kalanchoe gracilis, Da-Huan-Hun, is a Chinese folk medicine for treating pain and inflammation, exhibiting antioxidant and anti-inflammatory activities. Our prior report (2012) cited K. gracilis leaf extract as moderately active against EV71 and CoxA16. This study further rates antienteroviral potential of K. gracilis stem (KGS) extract to identify potent antiviral fractions and components. The extract moderately inhibits viral cytopathicity and virus yield, as well as in vitro replication of EV71 (IC50 = 75.18 μ g/mL) and CoxA16 (IC50 = 81.41 μ g/mL). Ethyl acetate (EA) fraction of KGS extract showed greater antiviral activity than that of n-butanol or aqueous fraction: IC50 values of 4.21 μ g/mL against EV71 and 9.08 μ g/mL against CoxA16. HPLC analysis, UV-Vis absorption spectroscopy, and plaque reduction assay indicate that eupafolin is a vital component of EA fraction showing potent activity against EV71 (IC50 = 1.39 μ M) and CoxA16 (IC50 = 5.24 μ M). Eupafolin specifically lessened virus-induced upregulation of IL-6 and RANTES by inhibiting virus-induced ERK1/2, AP-1, and STAT3 signals. Anti-enteroviral potency of KGS EA fraction and eupafolin shows the clinical potential against EV71 and CoxA16 infection.
    Full-text · Article · Sep 2013 · Evidence-based Complementary and Alternative Medicine
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