No abstract

Oxidative stress has been implicated in various pathological conditions including cancer. However, the human body has an intrinsic ability to fight against oxidative stress. A wide array of phase 2 detoxifying or antioxidant enzymes constitutes a fundamental cellular defense system against oxidative and electrophilic insults. Transcriptional activation of genes encoding detoxifying and antioxidant enzymes by NF-E2 related factor 2 (Nrf2), a member of the cap'n'collar family of basic leucine zipper transcription factors, may protect cells and tissues from oxidative damage. Many chemopreventive and chemoprotective phytochemicals have been found to enhance cellular antioxidant capacity through activation of this particular transcription factor, thereby blocking initiation of carcinogenesis. A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. Components of the cell signaling pathways, especially those that converge on redox-sensitive transcription factors, including nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) involved in mediating inflammatory response, have been implicated in carcinogenesis. A wide variety of chemopreventive and chemoprotective agents can alter or correct undesired cellular functions caused by abnormal proinflammatory signal transmission mediated by inappropriately activated NF-kappaB and AP-1. The modulation of cellular signaling by anti-inflammatory phytochemicals hence provides a rational and pragmatic strategy for molecular target-based chemoprevention.

Epigallocatechin 3-gallate (EGCG), the major polyphenol found in green tea, exerts antiproliferative and proapoptotic effects in many cancer cells. However, we found that among many cancer cells human lung adenocarcinoma A549 cells are markedly resistant to apoptosis induction by EGCG (even at 100 M for 72 h). Heme oxygenase-1 (HO-1) induced by stress stimuli represents a prime cellular defense mechanism, but it may be associated with enhanced cell proliferation and chemoresistance in some cancer cells. Because we found that A549 cells constitutively overexpress HO-1 and its associated transcription factor Nrf2, we tested an hypothesis that EGCG resistance in these cells may be linked with Nrf2-mediated HO-1 overexpression. HO-1 inhibition with tin-protoporphyrin IX and silencing with RNA interference rendered cells more sensitive to apoptosis induction by EGCG and classical prooxidants. Interestingly, EGCG at high concentration (>200 M) induced apoptosis by suppressing expression of HO-1 protein and mRNA, and this effect correlated with a decrease in both Nrf2-ARE binding and HO-1-ARE-luciferase activity, suggesting Nrf2-driven transcriptional activation of ho-1. Because we observed notably high levels of phosphorylated protein kinase C␣ and its suppression by EGCG and deferoxamine (an iron chelator), a possible mechanism involving phosphorylated protein kinase C␣ and iron in Nrf2-HO-1 activation was further investigated. Collectively, our findings suggest that Nrf2-mediated HO-1 overexpression confers resistance to apoptosis induction by EGCG; therefore, its inactivation may be a target for overcoming the resistance to chemoprevention and chemotherapy.Epigallocatechin 3-gallate (EGCG), 2 the major polyphenol found in green tea, is a widely studied cancer chemopreventive agent with potential anticancer activity. The major mechanism of EGCG-mediated anticancer effects is considered to be related to induction of apoptosis (1, 2). Studies have shown differential sensitivity among different tumor cells or tumor cells versus normal cells to EGCG (1, 2). In particular, in many cancer cells EGCG has been shown to modulate multiple and often different signal transduction pathways. The reason for these observed differences is not clear but may be because of the differential oxidative status imposed by EGCG in various cell types or cell type-specific expression of endogenous antioxidant defense enzymes.Heme oxygenase-1 (HO-1) is known to be highly induced by a variety of stress stimuli and many cancer chemopreventive agents, and it represents a prime cellular defense mechanism against oxidative stress via antioxidant function of its catalytic products like bilirubin and carbon monoxide (CO) with concomitant induction of iron sequestering ferritin (3, 54). On the contrary, its overexpression in human cancers may offer cancer cells a growth advantage and cellular resistance against chemotherapy and photodynamic therapy (4, 5). Because the growth of most tumors depends on HO-1 (6), it is also considered as a target for canc...

Inflammatory tissue injury has been implicated in tumor promotion and progression. 3,5,4'-trihydroxy-trans-stilbene (resveratrol) and 3,4,3', 5'-tetrahydroxy-trans-stilbene (piceatannol), 2 structurally related plant polyphenols, have been reported to possess antioxidant, anti-inflammatory, and chemopreventive properties. This study was aimed at investigating the possible protective effects of resveratrol and piceatannol against dextran sulfate sodium (DSS)-induced inflammation in mouse colonic mucosa. Administration of DSS (2.5%) in drinking water for 7 days to male ICR mice resulted in colitis and elevated expression of inducible nitric oxide synthase (iNOS) and activation of nuclear factor-kappa B (NF-kappaB), a major transcription factor known to upregulate proinflammatory gene expression. Phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription-3 (STAT3) was also enhanced after DSS treatment. Oral administration of resveratrol or piceatannol (10 mg/kg body weight each) for 7 constitutive days attenuated the DSS-induced inflammatory injury, upregulation of iNOS expression, and activation of NF-kappaB, STAT3, and ERK.

H. pylori-induced STAT3 activation is mediated, at least in part, through ROS-induced upregulation of IL-6 expression. These findings provide a novel molecular mechanism responsible for H. pylori-induced gastritis and gastric carcinogenesis.