Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

Abstract

Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two α,β unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2–related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D–treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2′-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…Two fractions, namely avicin D and avicin G were identified as bioactive [28][29][30]. Subsequent studies with avicins revealed its dual role as a potent inhibitor of activation of NF-jB [31] and activate NF-E2-related factor 2 (Nrf2) [32] in a redox-dependent manner, accounting for its Fig. 2.…”

“…anti-inflammatory [33] and antioxidant properties, respectively [32] probably by its ability to interact with critical cysteine residues. Interstingly, Haridas et al showed that avicins interact with and modify cysteine residues in a bacterial system with redox sensitive transcritptional activator, OxyR of Escherichia coli as a target, wherein the distal portion of the avicin side-chain formed a reversible and covalent thioester bond with the critical cysteine (SH) on the OxyR molecule [34] that provide adaptive response to oxidative and nitrosative stress.…”

“…In a recent report, avicin D was shown to induce not only apoptotic but also autophagic cell death by the depletion of the cell energy supply, suggesting a potential therapeutic application of avicins in apoptosis-resistant cancer [36]. In addition to their cytotoxic properties, avicins possess cytoprotective effects against non-transformed cells, in part related to the activation of the transcription factor, Nrf-2 [32]. Activation of proteins downstream of Nrf2, such as glutathione peroxidase, heme-oxygenase, and thioredoxin reductase, accounts in part for the antioxidant, antimutagenic and tissue protective effects of avicins, both in vitro and in vivo [32,33].…”

“…In addition to their cytotoxic properties, avicins possess cytoprotective effects against non-transformed cells, in part related to the activation of the transcription factor, Nrf-2 [32]. Activation of proteins downstream of Nrf2, such as glutathione peroxidase, heme-oxygenase, and thioredoxin reductase, accounts in part for the antioxidant, antimutagenic and tissue protective effects of avicins, both in vitro and in vivo [32,33]. The studies indicated that avicins act as multifunctional compounds, and not only inhibit tumor cell growth but may also play a role in the maintenance of cellular homeostasis.…”

Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast

“…A series of studies with a recently discovered family of triterpenoid compounds, the avicins, have identified cancer and inflammatory diseases as potential clinical targets (1)(2)(3)(4)(5)(6). Originally isolated from the Australian desert tree Acacia victoriae, avicins have been shown to selectively inhibit the growth of tumor cells from a wide variety of tissue origins (1)(2)(3)(4)(5)(6). Moreover, avicin treatment resulted in a dramatic reduction in the frequencies of both H-ras mutations and aneuploidy in a mouse model for skin carcinogenesis (4), as well as decreased p53 mutations in a murine UVB skin model (3).…”