123 POSTER Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells

Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
Biochemical Pharmacology (Impact Factor: 5.01). 08/2006; 72(2):132-44. DOI: 10.1016/j.bcp.2006.04.019
Source: PubMed


Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory activity. In this study, Andro induced apoptosis in human cancer cells via activation of caspase 8 in the extrinsic death receptor pathway and subsequently with the participation of mitochondria. Andro triggered a caspase 8-dependent Bid cleavage, followed by a series of sequential events including Bax conformational change and mitochondrial translocation, cytochrome c release from mitochondria, and activation of caspase 9 and 3. Inhibition of caspase 8 blocked Bid cleavage and Bax conformational change. Consistently, knockdown of Bid protein using small interfering RNA (siRNA) technique suppressed Andro-induced Bax conformational change and apoptosis. In conclusion, the pro-apoptotic Bcl-2 family members (Bid and Bax) are the key mediators in relaying the cell death signaling initiated by Andro from caspase 8 to mitochondria and then to downstream effector caspases, and eventually leading to apoptotic cell death.

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    • "In addition, andrographolide has exhibited anti-cancer properties89. Andrographolide was shown to inhibit tumor growth by inducing cell cycle arrest1011 or apoptosis1213 in various types of cancer cells. Andrographolide also suppresses v-Src transformation, and sensitizes cancer cells to apoptosis mediated by the tumor necrosis factor-related apoptosis-inducing ligand14. "
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    ABSTRACT: The abnormal growth of vascular smooth muscle cells (VSMCs) is considered a critical pathogenic process in inflammatory vascular diseases. We have previously demonstrated that protein phosphatase 2 A (PP2A)-mediated NF-κB dephosphorylation contributes to the anti-inflammatory properties of andrographolide, a novel NF-κB inhibitor. In this study, we investigated whether andrographolide causes apoptosis, and characterized its apoptotic mechanisms in rat VSMCs. Andrographolide activated the p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. Phosphorylated p53 subsequently transactivated the expression of Bax, a pro-apoptotic protein. Transfection with pp2a small interfering RNA (siRNA) suppressed andrographolide-induced p38MAPK activation, p53 phosphorylation, and caspase 3 activation. Andrographolide also activated the Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1), and induced PP2A dephosphorylation, both of which were inhibited by the SHP-1 inhibitor sodium stibogluconate (SSG) or shp-1 siRNA. SSG or shp-1 siRNA prevented andrographolide-induced apoptosis. These results suggest that andrographolide activates the PP2A-p38MAPK-p53-Bax cascade, causing mitochondrial dysfunction and VSMC death through an SHP-1-dependent mechanism.
    Scientific Reports 07/2014; 4:5651. DOI:10.1038/srep05651 · 5.58 Impact Factor
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    • "Another study in the in vivo demonstrated that the 70% ethanol extract of A. paniculata and andrographlide increased the life spans of mice injected with thymoma cells [26]. Andrographolide induces apoptosis in human cancer cells via the activation of caspase 8, pro-apoptotic Bcl-2 family members Bax conformational change, release of cytochrome C from mitochondria and activation of caspase cascade [27] and also through the activation of tumor suppressor p53 by ROS-dependent c-Jun NH 2 -terminal kinase (JNK) activation, Figure 3 In vitro anticlastogenic effect of Andrographia paniculata extracts in the presence of S 9 mixture at 24, 48 and 72 h of treatment duration. Table 4 In vitro analysis of sister chromatid exchanges (SCE) after treatment with aflatoxin B1 along with Andrographia paniculata extract, in the presence of S 9 mix. "
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    ABSTRACT: Background The history of natural products used in ancient times and in folk medicine these days, around the world, is the basis for the use of many therapeutic drugs in modern day medicine. Andrographia paniculata belongs to the family Acanthaceae or Kalmegh and is commonly known as ‘king of bitters’. It is extensively used as home remedy for various diseases in Indian traditional system as well as in tribal system in India for multiple clinical applications. Aim In our present work, extracts of these ayurvedic plants were tested for their anticlastogenic, antimutagenic and anticarcinogenic properties against Aflatoxin B1 induced toxicity. Materials and methods We used the in vitro method i.e. human lymphocytes culture and in vivo method in bone marrow cells of albino mice, while the parameters studied included chromosomal aberrations (CA), sister chromatid exchanges (SCEs) and cell growth kinetics (RI) both in the presence as well as in the absence of exogenous metabolic activation system for in vitro studies, whereas total aberrant cells and the frequencies of aberrations were used for in vivo methods. Results A. paniculata extracts significantly reduced chromosomal aberrations from 35.0%, 62.0% and 69.0% level [at 24, 48, and 72 h due to Aflatoxin B1] to 21.72%, 44.0% and 52.0%, similarly sister chromatid exchanges were reduced from 14.60 per cell to 7.50 per cell at 48 h of treatments and replication index was enhanced in vitro for each concentration and duration of treatment. Conclusion In conclusion A. paniculata extracts significantly reduced the number of aberrant cells and frequencies of aberration per cell at each concentration and duration of exposure in vivo; similarly it reduced chromosomal aberrations and sister chromatid exchanges and replication index was enhanced in vitro that was statistically significant at <0.05 level.
    Egyptian Journal of Medical Human Genetics 04/2014; 15(2). DOI:10.1016/j.ejmhg.2013.12.006
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    • "Extensive research has revealed that Andrographis paniculata has a broad range of pharmacological effects such as antiinflammatory (Sheeza et al., 2006), antidiarrhoeal (Gupta et al., 1990), antibacterial, antiviral (Wiart et al., 2005), *Corresponding author; Tel: 91(891)2575781; Fax: 91(891) 2755580 antimalarial (Misra et al., 1992; Rahman et al., 1999), filaricidal, hepatoprotective (Trivedi and Rawal, 2001; Visen et al., 2007), cardiovascular (Zhang and Tan, 1997; Tan and Zhang, 2004), anticancer (Kumar et al., 2004; Rajagopal et al., 2003; Cheung et al., 2005; Li et al., 2007; Sukardiman et al., 2007; Zhon et al., 2006), male reproductive toxicity (Akbarsha and Murugaian, 2000), cytotoxicity (Nanduri et al., 2004), immunostimulatory (Calabrese et al., 2000; Basak et al., 1999; Iruretagoyena et al., 2005) and antifertility (Akbarsha et al., 1990) activities. In view of its wide variety of above biological activities and in continuation of our studies (Radhika et al., 2008) the efficacy of the A. paniculata stem and root chloroform extracts were screened for their antibacterial activity against gram positive bacteria Staphylococcus "
    01/2014; 03(04). DOI:10.4172/2167-0412.1000169
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