Andrographolide Inhibits IFN-γ and IL-2 Cytokine Production and Protects Against Cell Apoptosis

Laboratory of Molecular Pharmacology, Institute of Pharmacology, Faculty of Veterinary Science, Universidad Austral de Chile, Valdivia, Chile.
Planta Medica (Impact Factor: 2.15). 06/2005; 71(5):429-34. DOI: 10.1055/s-2005-864138
Source: PubMed


Andrographolide is the main labdane diterpene present in Andrographis paniculata. Two lines of evidence report immunostimulant and anti-inflammatory properties for andrographolide in different models. Using murine T-cells in vitro we demonstrated that andrographolide and to a lesser extent, 14-deoxyandrographolide (14-DAP), reduced significantly, in a dose-dependent manner, the IFN-gamma production induced by concanavaline A (CON-A), with an IC50 of 1.7 +/- 0.07 microM and 35.8 +/- 0.50 microM, respectively. Andrographolide, but not 14-DAP, inhibited partially the IL-2 production induced by CON-A. Andrographolide at doses of 5 and 10 microM reduced the extracellular-signal-regulated protein kinase (ERK1/2) phosphorylation induced by CON-A, whereas 14-DAP only reduced ERK1 and partially the ERK2 phosphorylation. The inhibition of ERK1/2 phosphorylation was associated to a decrease in the IFN-gamma production, due that UO126, a specific ERK1/2 inhibitor, also reduced the IFN-gamma production in murine T-cells induced by CON-A. Additionally, andrographolide and to a lesser extent 14-DAP, at doses of 50 microM and 100 microM, respectively, reduced the apoptosis induced by hydrocortisone and PMA in thymocytes, which was associated to a decrease in caspase-3 like activity. We conclude that both diterpenic labdanes isolated from A. paniculata can exert potent immunosuppressant effects without affecting the viability of the cells.

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    • "Andro may modify the p50 subunit of NF-kB in an antagonistic manner, and this mechanism may be the cause of its multiple activities [6]. Its drug activity is dependent on its concentration because it can suppress apoptosis in many cell types at certain concentrations [7], [8], [9], but it can also induce apoptosis at high concentrations [10], [11], [12]. Many studies have demonstrated that Andro effectively induces cell cycle arrest in several types of cancer cells at the G0/G1 stage [10], [13], [14] and in human hepatoma HepG2 cells at the G2/M phase [15]. "
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    ABSTRACT: Andrographolide (Andro) suppresses proliferation and triggers apoptosis in many types of cancer cells. Taxifolin (Taxi) has been proposed to prevent cancer development similar to other dietary flavonoids. In the present study, the cytotoxic and apoptotic effects of the addition of Andro alone and Andro and Taxi together on human prostate carcinoma DU145 cells were assessed. Andro inhibited prostate cancer cell proliferation by mitotic arrest and activation of the intrinsic apoptotic pathway. Although the effect of Taxi alone on DU145 cell proliferation was not significant, the combined use of Taxi with Andro significantly potentiated the anti-proliferative effect of increased mitotic arrest and apoptosis by enhancing the cleavage of poly(ADP-ribose) polymerase, and caspases-7 and -9. Andro together with Taxi enhanced microtubule polymerization in vitro, and they induced the formation of twisted and elongated spindles in the cancer cells, thus leading to mitotic arrest. In addition, we showed that depletion of MAD2, a component in the spindle assembly checkpoint (SAC), alleviated the mitotic block induced by the two compounds, suggesting that they trigger mitotic arrest by SAC activation. This study suggests that the anti-cancer activity of Andro can be significantly enhanced in combination with Taxi by disrupting microtubule dynamics and activating the SAC.
    PLoS ONE 01/2013; 8(1):e54577. DOI:10.1371/journal.pone.0054577 · 3.23 Impact Factor
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    • "In recent years, a plethora of studies have focused on the effects of ANDRO on apoptosis. ANDRO appears to suppress apoptosis in differentiated cells (Chen et al., 2004; Burgos et al., 2005; Lee et al., 2010a, 2010b, 2010c; Roy et al., 2011; Lee et al., 2010a, 2010b, 2010c). However , in all human cancer cells studied so far, ANDRO induces apoptosis either on its own (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; Yang et al., 2010; Pratheeshkumar et al., 2011) or in combination with other treatments (Zhou et al., 2008; Yang et al., 2009; Zhou et al., 2010; Hung et al., 2010). "
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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 · 2.70 Impact Factor
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    • "Both compounds are structurally similar, although AP1 present in larger quantities and contains a hydroxyl group and two additional hydrogen atoms. Besides its anticancer and antiviral effects (Geethangili et al., 2008), AP1 inhibits the innate immune response via its actions on macrophages, pro-inflammatory cytokines, and chemotaxis (Burgos et al., 2005; Qin et al., 2006; Tsai et al., 2004). It ameliorates hypoxia Life Sciences 90 (2012) 257–266 ⁎ Corresponding author at: Institute of Biochemical Sciences and Technology, "
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    ABSTRACT: To test the effects of andrographolide (AP1) and 14-deoxy-11,12-didehydroandrographolide (AP2) on pheochromocytoma cell line 12 (PC12) cells in an astrocyte-rich environment. The abilities of AP1 and AP2 to reduce the secretion of pro-inflammatory cytokines Interleukin (IL)-1, IL-6, and Tumor necrosis factor (TNF)-α from stimulated astrocytes were tested. In addition, the abilities of AP1 and AP2 to reduce oxidative stress in astrocytes were tested using an oxidative-sensitive fluorescent dye. The reduction of chondroitin sulfate proteoglycan (CSPG) in stimulated astrocytes was tested using the dot blot method. Reduction of H(2)O(2)-induced death was tested in PC12 cells. Astrocyte-conditioned medium (ACM) and TNF-α-stimulated astrocyte-conditioned medium (SACM) were used to assess the effects of AP2 on PC12 cells treated with H(2)O(2). AP1 and AP2 reduced pro-inflammatory cytokines, reactive oxygen species (ROS), and CSPG in TNF-α stimulated astrocytes. AP1 protected H(2)O(2)-treated PC12 cells cultured in ACM. Co-incubation of PC12 cells in H(2)O(2), and ACM collected from AP1 treated astrocytes did not prevent cell death. AP1 and AP2 effectively ameliorated astrocytic pro-inflammatory reactions and prevented PC12 cell death with different efficacies. These compounds may be candidates for treatment of spinal-cord injury and neurodegeneration.
    Life sciences 11/2011; 90(7-8):257-66. DOI:10.1016/j.lfs.2011.11.004 · 2.70 Impact Factor
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