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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: 4.65). 08/2006; 72(2):132-44. DOI: 10.1016/j.bcp.2006.04.019
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ABSTRACT 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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    • "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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    • "Andrographolide inhibited cell cycle progression in human colorectal carcinoma and hepatoma cells [27] [28]. Furthermore, andrographolide induced the apoptosis of human hepatoma HepG2 cells via the caspase 8-dependent activation of pro-apoptotic Bcl-2 family members [29] and sensitized cancer cells to TRAIL-induced apoptosis in a p53-dependent manner [30]. Andrographolide also promoted autophagic cell death and increased ROS in human liver Fig. 1. "
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    ABSTRACT: Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.
    Biochemical pharmacology 10/2013; 87(2). DOI:10.1016/j.bcp.2013.10.014 · 4.65 Impact Factor
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    • "This confirms our earlier observation of G2/M arrest in ANDRO-treated HepG2 cells, and suggests that this phenomenon is a general response by the hepatoma cells to ANDRO. This sets hepatocellular carcinoma apart from a vast number of cell lines of diverse histological origins, which are induced to apoptosis on ANDRO treatment (Cheung et al., 2005; Kim et al., 2005; Zhou et al., 2006; Harjotaruno et al., 2007; Li et al., 2007a, 2007b, 2007c; Ji et al., 2007; Zhao et al., 2008; Pratheeshkumar et al., 2011; Yang et al., 2009). "
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    ABSTRACT: AIMS: Andrographolide (ANDRO) is emerging as a promising anti-tumour compound. While it causes apoptosis in most cancer cells, andrographolide induces cell cycle arrest in hepatocellular cancer lines. In this study, we studied the effect of andrographolide on hepatocellular cancers and other cancer types, and elucidated the possible hepatoma-specific features of andrographolide toxicity. MAIN METHODS: We compared the responses of a panel of human cell lines to andrographolide treatment by using flow cytometry, cell synchronisation and time-lapse microscopy. We have also examined their expression of cell cycle-related proteins and proteome changes after andrographolide treatment. KEY FINDINGS: Andrographolide exerts its effect on hepatocellular cancer cells through cell cycle arrest and not apoptosis. In HepG2 cells, it blocks G2 cells from entering mitosis and prevents mitosis from completion. This might be due to the disruption of mitotic spindle during metaphase. Despite the dramatic differences in their responses to andrographolide, HepG2 and HeLa cells display similar biochemical consequences. Andrographolide induces DNA damages, as indicated by the expression of phospho-H2AX in both cell lines. Proteomic experiments show that heme oxygenase 1 and heat shock protein 70 are among the proteins induced by andrographolide, which indicate the possible role of oxidative stress in the anti-cancer mechanism of this drug. SIGNIFICANCE: Andrographolide can invoke different cellular responses depending on the biochemical and physiological context in different cell and cancer types, and reveal an additional dimension of the therapeutic applications of this compound.
    Life sciences 04/2012; 91(15-16). DOI:10.1016/j.lfs.2012.04.009 · 2.30 Impact Factor
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