Modulation of signal transduction pathways by dietary cancer chemopreventive agents

The means by which the dietary cancer chemopreventive agents, curcumin, epigallocatechin-3-gallate (EGCG) and indole-3-carbinol (I3C) inhibit growth of human breast cell lines was investigated by examining their effects on various signal transduction pathways.;Curcumin inhibited the growth of HBL 100, T47D and MDA 468 cell lines to a similar extent (IC50 5M), while EGCG and I3C were most effective against the MDA 468 line (IC50 10M and 40M respectively). Curcumin inhibited epidermal growth factor (EGF)-stimulated phosphorylation of the EGF receptor (EGFR) in MDA 468 cells, phosphorylation and activity of extracellular regulated kinases (ERK) 1 and 2 in all three cell lines and Akt phosphorylation induced by several agents in HBL 100 cells. Curcumin inhibited the ability of anisomycin to activate c-jun N terminal kinase (JNK) and MAPK kinase 4 (MKK4), although it did not inhibit activation of p38. Further studies suggested that the target curcumin upstream of JNK may lie at the MAPK kinase kinase (MEKK) level. EGCG did not inhibit EGFR or ERK phosphorylation. Instead an increase in phosphorylation was observed. Nor did this agent inhibit JNK activity in pre-treated cells, although inhibition was observed when it was added directly to the assay. Similarly EGCG was a potent inhibitor of p38 activity in vitro, but did not affect its ability to activate the downstream kinase MAPK activating protein kinase-2 (MAPKAP K2) when added to cells. I3C had no effect on ERK phosphorylation, JNK or p38 activity. The global effect of curcumin treatment (10M) on transcription was investigated using cDNA microarrays. Several genes were shown to be affected, including downregulation of a number of matrix metalloproteinases.