Cucurbitacin B, a natural triterpenoid is well known for its strong anticancer activity, and recent studies showed that cucurbitacicn B inhibits JAK/STAT3 pathway. In this study, we demonstrate for the first time that cucurbitacin B is also a potent inhibitor of NF‐κB activation. Our results showed that cucurbitacin B inhibited TNF‐α‐induced expression of NF‐κB reporter gene and NF‐κB target genes in a dose‐dependent manner, however, cucurbitacin B did not prevent either stimuli‐induced degradation of IκBα or nuclear translocation and DNA‐binding activity of NF‐κB. On the other hand, cucurbitacin B dose‐dependently suppressed not only NF‐κB activation induced by overexpression of RelA/p65 but also transactivation activity of RelA/p65 subunit of NF‐κB. Consistently, treatment of HeLa cells with cucurbitacin B significantly suppressed TNF‐α‐induced activation of Akt and phosphorylation of Ser536 in RelA/p65, which is required for transactivation activity. Consequently, cucurbitacin B inhibited TNF‐α‐induced expression of NF‐κB dependent anti‐apoptotic proteins such as c‐IAP1, c‐IAP2, XIAP, TRAF1, and TRAF2 and sensitized TNF‐α‐induced cell death. Taken together, our results demonstrated that cucurbitacin B could be served as a valuable candidate for the intervention of NF‐κB‐dependent pathological condition such as cancer.
Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Current treatment of this cancer generally employs surgical resection combined with chemotherapy using cytotoxic drugs and radiation therapy. Because this therapy is only moderately successful for late stage cancers, novel approaches to the treatment of colorectal cancer are required. Falcarindiol is a natural polyyne from medicinal plant Oplopanax horridus that has been widely used by indigenous people for a variety of diseases. We show that Falcarindiol can selectively kill colon cancer cells but not the normal colon cells. We further show that the observed cell death is mediated through the induction of Endoplasmic Reticulum (ER) stress. We further show that inhibition of ER stress significantly block Falcarindiol-induced colon cancer cell death while knockdown of GRP78, which sensitizes cells to ER stress induced cell death, significantly enhances Falcarindiol-induced cell killing. Interestingly, we find that Falcarindiol exhibits synergistic anticancer activity with 5-FU, a chemotherapeutic drug for colon cancer. These results suggest that Falcarindiol is potentially a valuable candidate that can be used to in the treatment of colon cancer either alone or in combination with current anti-colon cancer agent such as 5-FU. Key words: Falcarindiol; Colon cancer; ER Stress; Cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1973. doi:1538-7445.AM2012-1973
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