inflammation ͉ Nrf2 Keap1 ͉ oxidative stress ͉ phase 2 enzymes ͉ NAD(P)Hquinone acceptor oxidoreductase

Considerable interest has emerged in the possibility of exploiting the apoptotic effects of TRAIL 1 for the treatment of cancer. TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that is capable of inducing apoptosis (1).The apoptosis-inducing receptors for TRAIL include Trail-R1 (DR4) and Trail-R2 (DR5), which are transmembrane type I receptors expressed on the surface of many types of cell. However, TRAIL also binds to non-apoptosis-inducing decoy receptors, which compete with death receptors for ligand and suppress apoptosis, including DcR1, DcR2, and osteoprotegerin (reviewed in Refs. 2 and 3). Empiric analysis of the effects of TRAIL on normal and malignant cells has provided compelling evidence that recombinant TRAIL protein preferentially induces apoptosis of cancer cells without harming most types of untransformed cells (reviewed in Ref. 2). When properly prepared and purified, recombinant trimeric TRAIL also lacks significant toxicity in primate species that possess receptors capable of binding human TRAIL (4, 5).Preclinical studies of recombinant TRAIL (extracellular domain) in mice have demonstrated impressive anti-tumor activity and synergy with cytotoxic anticancer drugs (6). However, not all tumors respond to TRAIL. This lack of response may be attributed either to unfavorable ratios of death and decoy receptors or because of intracellular resistance mechanisms (3, 7-10). With respect to intracellular resistance mechanisms, the FLIP protein has been identified as a blocker of apoptosis induced by TNF family death receptors (reviewed in Ref. 11). FLIP binds to and neutralizes adapter proteins and procaspases normally recruited to the cytosolic domains of apoptosis-inducing TRAIL receptors upon ligand stimulation, thus interrupting early steps in TRAIL signaling. Furthermore, overexpression of FLIP protein has been documented in cancers (12).PPAR␥ is a member of the steroid/retinoid superfamily of ligand-activated transcription factors. Agonistic ligands of PPAR␥ include modified fatty acids, cyclopentenone-containing prostaglandins, triterpenoids, and the thiazolidinediones, a class of insulin-sensitizing drugs used in the treatment of type II diabetes (reviewed in Ref. 13). Anti-tumor properties of PPAR␥ agonists have been reported. For example, thiazolidinediones have been shown to suppress the growth of human colon and breast cancer cell lines in vitro and in vivo in the mouse (14, 15), and a member of a new class of PPAR␥ agonists (tyrosine analogs) suppresses mammary carcinogenesis in a standard rat model (16). However, troglitazone increases incidence of colonic polyps in a mouse model in which one allele of adenomatous polyposis coli is inactive (17, 18), suggesting complex effects on neoplasia. Moreover, the concentrations of thiazolidinediones required for some apoptotic effects are beyond clinically attainable ranges (15).Here we explored the effects of PPAR␥ ligands on TRAILinduced apoptosis in epithelial cancers cell lines. Our findings demonstrate a new PPAR␥-inde...

The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids. (Cancer Res 2005; 65(11): 4789-98)

Mortality that results from the common forms of cancer is still unacceptably high. Despite immense advances in the understanding of the mechanisms of carcinogenesis, in bringing potent new drugs to the clinic and in treating several relatively rare forms of cancer, overall mortality statistics are unlikely to change in a fundamental way until there has been a re-orientation of emphasis in cancer research that will direct greater resources towards prevention of new disease, rather than treatment of end-stage disease.

In this short article, we review the conceptual basis for chemoprevention of cancer, the proven clinical efficacy of this concept, and current trends to develop new chemopreventive agents based on understanding of their mechanisms of action. Four classes of new agents, namely selective inhibitors of cyclooxygenase-2, selective estrogen receptor modulators, rexinoids (retinoids that bind selectively to the receptors known as RXRs) and ligands for the peroxisome proliferator-activated receptor-gamma are discussed in detail. The importance of developing totally new classes of chemopreventive agents is stressed, with particular emphasis on the potential usefulness of new synthetic triterpenoids derived from naturally occurring molecules.

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We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC(50) = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC(50) = 1 microM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-gamma-induced mouse peritonitis.