科研之友
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摘要
Systems biology and molecular network modeling are important tools that are finding application in anticancer drug discovery. These technologies can be utilized to map and evaluate the entire set of pathways modulated by drugs in cancer cells without loosing key details. Such integrated approaches are especially useful in understanding the mechanism of action of agents that do not have a defined target. Our novel compound CDF (a synthetic analogue of curcumin), is one such multi-targeted agent with proven anti-cancer activity in vitro and in vivo. However, its mechanism of action is not fully understood, and thus a thorough analysis of key pathways targeted by CDF would be important for developing targeted and tailored therapy in the future. Applying Ingenuity Pathway Analysis (IPA), we have mapped the pathways altered by CDF treatment of BxPC-3 pancreatic cancer (PC) cells. Illumina HT-12 microarrays were performed on RNA extracted from CDF treated cells. IPA analysis of gene expression at early time point (24 hrs) revealed deregulation of genes in the c-Myc hub. Western blot analysis validated the activation of c-Myc, p73 and its downstream pro-apoptotic effector Bax with simultaneous down-regulation of Bcl-2 in two distinct pancreatic cancer cell lines (BxPC-3 and Colo-357). In order to further delineate the role of c-Myc in inducing apoptosis, siRNA silencing technology was used. As expected, c-Myc siRNA knockdown resulted in abrogation of the growth inhibitory and apoptotic potential of CDF. In conclusion, our results demonstrate a novel c-Myc driven apoptotic network activated by CDF in PC cells that is independent of wild-type p53, and thus warrants further investigation on the clinical utility of CDF.
- 出版日期2011
