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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

The present study demonstrated the considerable role of the mitochondrial apoptotic pathways in apoptosis induced by damnacanthal in MCF-7 cells. apoptosis through the activation of p21 and TAK-285 caspase-7. (Rubiaceae), commonly known as noni, is a small evergreen tree or shrub that is widely distributed throughout the pacific islands, Southeast Asia and other tropical and semitropical areas. It has been widely used in therapeutic preparations for centuries, owing to its anti-inflammatory, antibacterial, antiviral, antifungal and antitumor properties (6C9). Damnacanthal, an anthraquinone compound, was isolated from the roots of release, regulation of TAK-285 protein kinase C isoform expression, inhibition of NF-B and suppression of activator protein 1 GCSF (17C19). The results of the current study were consistent with our previous study, as damnacanthal induced apoptosis in HL-60 and Wehi-3B cells (10). Further investigations were performed to highlight the apoptotic pathways involved in the apoptosis induced by damnacanthal in MCF-7 cells. Previous studies have revealed that caspases are critical in executing apoptosis (20). In order to gain further insight into the mechanism of the signaling cascade, the present study examined the molecular sequence of events in damnacanthal-induced apoptosis. Apoptosis may occur via two fundamental pathways: i) death receptor or extrinsic pathway; and ii) mitochondrial or intrinsic pathway. The present study demonstrated the considerable role of the mitochondrial apoptotic pathways in apoptosis induced by damnacanthal in MCF-7 cells. Damnacanthal-mediated activation of Bax, p21 and caspase-7 was identified in MCF-7 cells. The activation of TAK-285 p21 and caspase genes stimulates p53 phosphorylation (21). Although multiple pathways contribute to the modulation of p53 (22), the current study investigated the expression of p21 as one of the upstream molecules of p53. The results demonstrated that p21-p53 signaling is one of the key pathways in mediating damnacanthal-induced apoptosis. In addition, the role of p21 in the transcription of the p53-regulated Bax gene is likely to involve p53 phosphorylation (23). The increased damnacanthal-dependent p53 protein levels are consistent with the damnacanthal-dependent transcriptional induction of Bax. Extensive analyses of damnacanthal-dependent modifications of p53 are in progress to link p21 activity TAK-285 with p53 function in damnacanthal-mediated apoptosis. Although modulation of p21 and p53 signaling is common, the current study established connections between well-known proapoptotic molecules in the damnacanthal-induced apoptosis. In conclusion, damnacanthal, a bioactive compound from noni roots, enhanced the expression of p21 and caspase-7. Overexpression of p21 directly activates transcription and expression of p53 and, subsequently, increases apoptosis in human breast cancer MCF-7 TAK-285 cells. These results are likely to highlight the potential benefits of damnacanthal for further preclinical or clinical practice and damnacanthal may be a useful cancer prevention/therapeutic agent in human breast carcinoma. Acknowledgements The authors would like to thank the Ministry of Higher Education (Putrajaya, Malaysia) for financial assistance through the Fundamental Grant Research Scheme (no. 03-10-10-964FR)..