Deguelin, an Akt inhibitor, down-regulates NF-κB signaling and induces apoptosis in colon cancer cells and inhibits tumor growth in mice

Background: Deguelin, a naturally occurring rotenoid, is known to be an Akt Inhibitor and to have an anti-tumor effect on several cancers.

Aims: This study was performed to elucidate the effect of deguelin on apoptotic pathways related to NF-κB signaling in colon Cancer cells and on the anti-tumor effect in colon Cancer xenograft mice.

Methods: We studied COLO 205 and HCT116 cells in the presence or absence of deguelin. NF-κB signaling was examined by real-time RT-PCR for interleukin (IL)-8, by Western blotting for IκB phosphorylation/degradation, and by the electrophoretic mobility shift assay. Cell death was determined by the MTT assay, and Apoptosis by Annexin V-FITC staining and Caspase-3 activity. We also assessed the expression of antiapoptotic and proapoptotic factors by use of RT-PCR. In colon Cancer xenograft mice, we evaluated the effect of deguelin on inoculated tumor growth, and apoptotic index was measured by the in vivo TUNEL assay.

Results: Deguelin significantly inhibited IL-8 gene expression, IκB phosphorylation/degradation, and DNA binding activity of NF-κB in colon Cancer cells. Deguelin induced cell death and Apoptosis in colon Cancer cells in a dose and time-dependent manner. Deguelin down-regulated expression of NF-κB-mediated antiapoptotic factors such as cFLIP, Bcl-2, and Bcl-X(L). In the colon Cancer xenograft model, the volume of the tumor treated with deguelin was significantly lower than that of the control, and the apoptotic index for deguelin-treated mice was much higher.

Conclusion: Deguelin might be a potential therapeutic agent for treatment of colorectal Cancer.