As also confirmed by western blot analysis, http://www.selleckchem.com/products/Calcitriol-(Rocaltrol).html a decreased expression of the PIK3R2 gene, an almost complete de pletion of the PI3K protein, and a 75% decrease of acti vated phospho Akt have been observed in D6 treated cells. In addition, a slight up modulation of PTEN gene expression was detected in our study. The I��B kinase NF ��B signalling pathway is also often altered in tumours and NF ��B can affect all six hallmarks of cancer through the transcriptional activation of genes associated with cell Inhibitors,Modulators,Libraries proliferation, angiogenesis, metastasis, tumour promotion, inflammation and suppression of apoptosis. PI3K and NF kB signalling pathways are functionally linked, being NF kB possibly activated by Akt kinase.

Our results show that, similarly to PIK3R2, NFKB1 gene expression Inhibitors,Modulators,Libraries is down regulated by D6 in melanoma cells, but it is unclear whether this could be due to the PI3K/Akt signalling repression. Deeper investigations should be made to shed light on this molecular event. However, it is interesting to underline that PI3K and NF kB pathways are both involved in curcumin anti tumour activity and inhibition of NF kB activation may ac count for curcumin efficacy on cancer cells and, specif ically, on human melanoma cells. As a consequence, it is likely that the curcumin analogue D6 shares some mechanisms Inhibitors,Modulators,Libraries of action with its natural compound, being even more effective in inhibiting tumour cells growth. It is noteworthy that neither PIK3R2 nor NFKB1 genes ex pression was modulated in D6 treated normal fibroblasts.

Based on these considerations, we can postulate that PI3K and Inhibitors,Modulators,Libraries NF kB signalling down regulation is strongly related to the anticancer activity of D6 on melanoma cells. A further consideration may be done about a possible re lationship between NFKB1 under expression and p53 sig nalling up regulation. An intense crosstalk exists among these two transcription factors that activate Inhibitors,Modulators,Libraries the expression of genes with opposite functions. They are indeed competi tors for the transcriptional coactivator p300/CBP and, depending upon which of them recruits this protein, different downstream pathways will be acti vated, resulting in either cell proliferation or growth arrest and apoptosis.

To this regard, a recent report by Sen and colleagues demonstrated that curcumin re verses doxorubicin resistance in breast cancer by inhibiting NF ��B activation and thus rescuing selleck chemicals p300 coactivator, which in turn becomes available to the p53 transcription factor, and finally allows p53 dependent transactivation of proapoptotic proteins such as Bax, PUMA and Noxa. Based on these observations down regulation of NF ��B by D6 would make the coactivator p300 available for recruit ment by p53, thus favouring transactivation of its target genes that triggers antiproliferative and proapoptotic activ ity.