Signal transduction events elicited by cancer prevention compounds

Many chemopreventive agents have been shown to modulate gene expression inc luding induction of phase II detoxifying enzymes, such as glutathione S-tra nsferases (GST) and quinone reductases (QR). Induction of phase II enzymes in general leads to protection of cells/tissues against exogenous and/or en dogenous carcinogenic intermediates. The antioxidant or electrophile respon se element (ARE/EpRE) found at the 5 ' -flanking region of these phase II g enes may play important role in mediating their induction by xenobiotics in cluding chemopreventive agents. Members of the basic leucine zipper (bZIP) transcription factor, Nrf2 which heterodimerizes with Maf G/K, are found to bind to the ARE, and transcriptionally-activated ARE. Recently, we showed that the mitogen-activated protein kinases (MAPK) were activated by phase I I gene inducers such as phenolic antioxidant butylated hydroxyanisol (BHA) and isothiocyanate sulforaphane (SUL), and involved in the transcription ac tivation of ARE-mediated reporter gene. Transfection studies with wild-type and dominant negative mutants of Nrf2 and MAPK showed synergistic response during co-transfection as well as to phase II gene inducers. However, incr easing the concentrations of these compounds such as BHA. the activities of cell death signaling molecules, caspases, were stimulated and resulted in apoptotic cell death. At these concentrations, BHA stimulated loss of mitoc hondrial membrane potential, cytochrome c release, and activation of caspas e 3, 8 and 9 preceding apoptosis. Further increase in concentrations led to rapid cell necrosis. A model is proposed for BHA and SUL, in that at low c oncentrations, these potential chemopreventive agents may modulate MAPK pat hway leading to transcription activation of Nrf2 and ARE with subsequent in duction of cellular defensive enzymes including phase II detoxifying enzyme s as well as other defensive genes, which may protect the cells against cel lular injury. which is a homeostatic response. At higher concentrations, th ese agents may activate the caspase pathways, leading to apoptosis, a poten tial beneficial effect if occurs at preneoplastic/neoplastic tissues, but a potential cytotoxic response if occurs in normal tissues. On the other han d. some phenolic compounds such as resveratrol inhibits TPA- or UV-induced AP-1-mediated activity through the inhibition of c-Src non-receptor tyrosin e kinase and MAPK pathways. It is possible that in proliferating or stimula ted cells, these chemopreventive compounds may block proliferation by inhib iting these signaling kinases. whereas in non-proliferating or quiescent ce lls, some of these compounds may activate these signaling kinases leading t o gene expression of cellular defensive enzymes such as phase II detoxifyin g enzymes. The studies of these and other signaling pathways may yield insi ghts into the development of potential chemopreventive compounds. (C) 2001 Elsevier Science B.V. All rights reserved.