Review

Archives of Pharmacal Research

, Volume 23, Issue 1, pp 1-16

First online:

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

  • Ah-Ng Tony KongAffiliated withCenter for Pharmaceutical Biotechnology, MC 870 Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago Email author 
  • , Rong YuAffiliated withCenter for Pharmaceutical Biotechnology, MC 870 Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago
  • , Chi ChenAffiliated withCenter for Pharmaceutical Biotechnology, MC 870 Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago
  • , Sandhya MandlekarAffiliated withCenter for Pharmaceutical Biotechnology, MC 870 Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago
  • , Thomas PrimianoAffiliated withDepartment of Molecular Genetics, College of Medicine, University of Illinois at Chicago

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Abstract

Many natural products elicit diverse pharmacological effects. Using two classes 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, ECG, and isothiocyanates; PEITC, sulforaphane), provided important insights into the signaling pathways induced by these compounds. At low concentrations, these chemicals may activate the MAPK (ERK2, JNK1, p38) leading to gene expression of survival genes (c-Fos, c-Jun) and defensive genes (Phase II detoxifying enzymes; GST, QR) resulting in survival and protective mechanisms (homeostasis response). Increasing the concentrations of these compounds will additionally activate the caspase pathway, leading to apoptosis (potential cytotoxicity). Further increment to suprapharmacological concentrations will lead to nonspecific necrotic cell death. The wider and narrow concentration ranges between the activation of MAPK/gene induction and caspases/cell death exhibited by phenolic compounds and isothiocyanates, respectively, in mammalian cells, may reflect their respective therapeutic windowsin vivo. Consequently, the studies of signaling pathways elicited by natural products will advance our understanding of their efficacy and safety, of which many may become important therapeutic drugs of the future.

Key words

MAPK Caspases Chemopreventive agents Phase II drug metabolizing enzymes Apoptosis