Signal transduction events elicited by natural products: Role of MAPK and caspase pathways in homeostatic response and induction of apoptosis

Many natural products elicit diverse pharmacological effects. Using two cla sses of potential chemopreventive compounds, the phenolic compounds and the isothiocyanates, we review the potential utility of two signaling events, the mitogen activated protein kinases (MAPKs) and the ICE/Ced-3 proteases ( caspases) stimulated by these agents in mammalian cell lines. Studies with phenolic antioxidants (BHA, tBHQ), and natural products (flavonoids; EGCG, EGG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrati ons, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gen e expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechani sms (homeostasis response). Increasing the concentrations of these compound s will additionally activate the caspase pathway, leading to apoptosis (pot ential cytotoxicity). Further increment to suprapharmacological concentrati ons will lead to nonspecific necrotic cell death. The wider and narrow conc entration ranges between the activation of MAPK/gene induction and caspases /cell death exhibited by phenolic compounds and isothiocyanates, respective ly, in mammalian cells, may reflect their respective therapeutic windows in vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of wh ich many may become important therapeutic drugs of the future.