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

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 windows in 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.

Flavonoids as Therapeutic Compounds Targeting Key Proteins Involved in Alzheimer’s Disease

“…104,105 It has been suggested that flavonoids and their metabolites may interact selectively with the MAPK signaling pathways. 102,106 The action of flavonoids on the ERK pathway 83,99,107−110 appears to be mediated by interactions with MAPK kinases MEK1 and MEK2 and potentially membrane receptors. 102,111,112 In fact, flavonoids have close structural homology to specific pharmacological modulators of ERK signaling such as PD98059 (2′-amino-3′-methoxyflavone).…”

“…102,106 The action of flavonoids on the ERK pathway 83,99,107−110 appears to be mediated by interactions with MAPK kinases MEK1 and MEK2 and potentially membrane receptors. 102,111,112 In fact, flavonoids have close structural homology to specific pharmacological modulators of ERK signaling such as PD98059 (2′-amino-3′-methoxyflavone). Moreover, activation of ERK can result in downstream activation of cAMP response element binding protein (CREB), which may lead to changes in synaptic plasticity and memory 113,114 and to upregulation of neuroprotective pathways.…”

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

“…For example, accumulating evidence suggests that flavonoids can interact selectively within MAPK signaling cascades in non-neuronal models [104,107]. This could have important implications with regard to their possible sites of action in neurons since members of the MAPK family are involved in signaling to neuronal survival, regeneration, and death [48,136,226].…”

Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1

“…It has been shown by several groups that the activation of these kinases by PEITC correlates with activation of the caspase‐dependent apoptotic pathway, and that chemical inhibition of these kinases blocks this process. For example, chemical inhibition of only JNK activity, and not p38 MAPK or ERK1/2, in human colon adenocarcinoma cells (HT‐29) reduced PEITC‐induced apoptosis 79a. Inhibition of the p38 MAPK with the inhibitor SB202190 did not prevent apoptosis activation by PEITC in PC3 cells; however, treatment with the ERK1/2 inhibitor, PD98059 achieved this effect 82.…”

“…Additionally, PEITC induces extrinsic and intrinsic apoptotic pathways in cancer cells77 by promoting ROS production,77, 78 activating the MAPKs pathways,79 downregulating the anti‐apoptotic proteins Bcl‐2 and Bcl‐x,80 and activating the pro‐apoptotic proteins Bax and Bak 81. Exposure to PEITC causes the activation of stress‐activated MAPKs such as c‐Jun N‐terminal kinase (JNK),77a p38 MAPKs,56, 82 and extracellular signal‐regulated kinase1/2 (ERK1/2) 83.…”