Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells
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.
SourceAvailable from: Yu-Jen Wu[Show abstract] [Hide abstract]
ABSTRACT: 13-acetoxysarcocrassolide (13-AC), an active compound isolated from cultured Formosa soft coral Sarcophyton crassocaule, was found to possess anti-proliferative and apoptosis-inducing activities against AGS (human gastric adenocarcinoma cells) gastric carcinoma cells. The anti-tumor effects of 13-AC were determined by MTT assay, colony formation assessment, cell wound-healing assay, TUNEL/4,6-Diamidino-2-phenylindole (DAPI) staining, Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and flow cytometry. 13-AC inhibited the growth and migration of gastric carcinoma cells in a dose-dependent manner and induced both early and late apoptosis as assessed by flow cytometer analysis. 13-AC-induced apoptosis was confirmed through observation of a change in ΔΨm, up-regulated expression levels of Bax and Bad proteins, down-regulated expression levels of Bcl-2, Bcl-xl and Mcl-1 proteins, and the activation of caspase-3, caspase-9, p38 and JNK. Furthermore, inhibition of p38 and JNK activity by pretreatment with SB03580 (a p38-specific inhibitor) and SP600125 (a JNK-specific inhibitor) led to rescue of the cell cytotoxicity of 13-AC-treated AGS cells, indicating that the p38 and the JNK pathways are also involved in the 13-AC-induced cell apoptosis. Together, these results suggest that 13-AC induces cell apoptosis against gastric cancer cells through triggering of the mitochondrial-dependent apoptotic pathway as well as activation of the p38 and JNK pathways.Marine Drugs 10/2014; 12(10):5295-315. DOI:10.3390/md12105295 · 3.51 Impact Factor
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ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. HIF-1α is one of the most compelling anticancer targets. Andrographolide (Andro) was newly identified to inhibit HIF-1 in T47D cells (a half maximal effective concentration [EC50] of 1.03×10(-7) mol/L), by a dual-luciferase reporter assay. It suppressed HIF-1α protein and gene accumulation, which was dependent on the inhibition of upstream phosphatidylinositol 3-kinase (PI3K)/AKT pathway. It also abrogated the expression of HIF-1 target vascular endothelial growth factor (VEGF) gene and protein. Further, Andro inhibited T47D and MDA-MB-231 cell proliferation and colony formation. In addition, it exhibited significant in vivo efficacy and antitumor potential against the MDA-MB-231 xenograft in nude mice. In conclusion, these results highlighted the potential effects of Andro, which inhibits HIF-1, and hence may be developed as an antitumor agent for breast cancer therapy in future.OncoTargets and Therapy 01/2015; 8:427-35. DOI:10.2147/OTT.S76116 · 1.34 Impact Factor
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ABSTRACT: Non-polar (dichloromethane) and polar (MeOH and aqueous) extracts of Andrographis paniculata (whole plant) were evaluated for in vitro antibacterial activity against 10 skin disease causing bacterial strains (6 gram positive strains; Staphylococcus saprophyticus, Staphylococcus epidermis, Staphylococcus aureus, Streptococcus pyogenes, Bacillus anthracis, Micrococcus luteus) and 4 gram negative strains (Proteus mirabilis, Proteus vulgaris, Neisseria meningitis, Pseudomonas aeruginosa) using disc diffusion method at three different concentrations; 1000, 500 and 250 µg/disc respectively. The extracts showed significant antibacterial activities against both Gram-positive and Gram-negative bacterial strains tested. Highest significant antibacterial activity was exerted by the aqueous extract against M. luteus at 1000 µg/disc and the least activity was exhibited by the DCM extract against N. meningitis at 250 µg/disc. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) observed were between 150 to 300 µg/ml and 250 to 400 µg/ml respectively, depending on microorganism and the nature of various extracts. Time-kill experiments indicated that A. paniculata extracts have bactericidal characteristic against most of the Gram positive bacteria and bacteriostatic activity against both Gram negative and Gram positive bacteria. These results candidly suggest the presence of promising antibacterial substances in the polar as well as non-polar extracts which could be the source of potential phytomedicine for the treatment of skin infections caused by the pathogenic bacterial strains. Our findings explicitly support its traditional claims and form a strong basis for further sincere efforts to explore A. paniculata's antibacterial potential to treat skin frailties efficaciously.Journal of medicinal plant research 01/2011; 5(1):7-14. · 0.88 Impact Factor