Curcumin, a polyphenol derived from the plant Curcuma longa and used as a spice, may be useful for dietary cancer prevention since it possesses strong antitumor activities. We addressed the molecular mechanisms of the cancer chemopreventive properties of Curcumin and examined its action in vitro in breast cancer cell lines of differing tumorigenicity and invasiveness (MDA-MB-231<MDA-MB-435) as well as in vivo in a mouse model of hematogenous metastasis. Prolonged exposure to Curcumin (24 hours) reduced cell viability which correlated with elevated lactate dehydrogenase activity in cell supernatants indicating cytotoxic effects. Curcumin strongly induced apoptosis in MDA-MB-231 cells and to a lesser extent in MDA-MB-435 cells as analyzed by flow cytometry of fragmented DNA containing cells. Additionally the polyphenol significantly inhibited migration and invasion through a reconstituted basement membrane. Reduced invasion can be attributed to reduced expression of matrix metalloproteinases (MMPs), which are the key enzymes for cellular invasion and metastasis. Curcumin reduced messenger RNA as well as protein expression and activity of MMP -1, -2, -3, and -9. In accordance to transcriptional down-regulation of MMPs, Curcumin reduced IκB phosphorylation and nuclear translocation of NFκB and decreased NFκB, AP-1 and CRE transcription factors present in nuclear extracts. Silencing of the p65 subunit of NFκB reduced MMP expression suggesting that the effect of Curcumin is mediated by NFκB. MDA-MB-435 cells express elevated levels of the anti-apoptotic factors bcl2 and birc5/survivin and are more resistant to the apoptotic effects of Curcumin. Consistently, NFκB activation in MDA-MB-435 cells was not affected by Curcumin and p65 silencing had no effect on MMP expression. The number but not growth, vitality or histology of lung metastases formed after intracardiac injection of MDA-MB-231 cells in immunodeficient mice was significantly reduced by Curcumin. These data show that Curcumin not only exerts anti-proliferative and pro-apoptotic activities but reduces metastatic dissemination most probably through down-regulation of NFκB/AP-1 dependent MMP transcription.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]