Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation

Surh, Young‐Joon; Chun, Kyung‐Soo; Cha, Hyun‐Suk; Han, Seong‐Su; Keum, Young‐Sam; Park, Kwang-Kyun; Lee, Sang Sup

doi:10.1016/s0027-5107(01)00183-x

Cited by 1,479 publications

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“…50,51 Studies analyzing the effect of RES on cardiovascular disease have also shown that this molecule inhibits lipid peroxidation by a pathway that involves NF-kB inactivation. 52,53 Therefore, the apoptosis induced by RES in MCF-7 cells could be mediated by Bcl-2 through a PI3K-and NF-kB-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

209

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionmentioning

confidence: 99%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

209

143

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“…Resveratrol has been reported to possess a variety of anti-inflammatory, antiplatelet and both pro-and antioestrogenic effects (Bertelli et al, 1996;Gehm et al, 1997;Jang et al, 1997;Uenobe et al, 1997). It exerts a wide variety of biological effects germane to cancer chemoprevention, including the inhibition of cytochrome P450 enzyme expression activity (Chun et al, 1999;Guengerich et al, 2003), induction of apoptosis (Mahyar-Roemer et al, 2001, modulation of components of the cell cycle machinery (Schneider et al, 2000;Wolter et al, 2001), decrease in cyclooxygenase 1 (COX-1) activity and COX-2 expression (Subbaramaiah et al, 1998;Mutoh et al, 2000;Li et al, 2002), antioxidation (Sgambato et al, 2001), inhibition of activities of protein kinase C and D (Haworth Revised 17 October 2003;accepted 17 November 2003 andAvkiran, 2001;Slater et al, 2003) and decrease in the activity of transcription factors NFkB and AP-1 (Surh et al, 2001;Banerjee et al, 2002). As is the case with many polyphenols with putative cancer chemopreventive properties, the systemic bioavailability of resveratrol is probably poor.…”

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confidence: 99%

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

et al. 2004

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Resveratrol (trans-3,5,4 0 -trihydroxystilbene) is a naturally occurring polyphenol with cancer chemopreventive properties in preclinical models of carcinogenesis, including those of colorectal cancer. Recently, a variety of analogues of resveratrol have been synthesised and investigated in in vitro assays. One analogue, 3,4,5,4 0 -tetramethoxystilbene (DMU 212), showed preferential growth-inhibitory and proapoptotic properties in transformed cells, when compared with their untransformed counterparts. As part of a chemoprevention drug development programme, the pharmacokinetic properties of DMU 212 were compared with those of resveratrol in the plasma, liver, kidney, lung, heart, brain and small intestinal and colonic mucosa of mice. DMU 212 or resveratrol (240 mg kg À1 ) were administered intragastrically, and drug concentrations were measured by HPLC. Metabolites were characterised by cochromatography with authentic reference compounds and were identified by mass spectrometry. The ratios of area of plasma or tissue concentration vs time curves of resveratrol over DMU 212 (AUC res /AUC DMU212 ) for the plasma, liver, small intestinal and colonic mucosa were 3.5, 5, 0.1 and 0.15, respectively. Thus, resveratrol afforded significantly higher levels than DMU 212 in the plasma and liver, while DMU 212 exhibited superior availability compared to resveratrol in the small intestine and colon. Resveratrol was metabolised to its sulphate or glucuronate conjugates, while DMU 212 underwent metabolic hydroxylation or single and double O-demethylation. DMU 212 and resveratrol inhibited the growth of human-derived colon cancer cells HCA-7 and HT-29 in vitro with IC 50 values of between 6 and 26 mM. In the light of the superior levels achieved in the gastrointestinal tract after the administration of DMU 212, when compared to resveratrol, the results provide a good rationale to evaluate DMU 212 as a colorectal cancer chemopreventive agent.

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“…Several studies have shown that curcumin (diferuloylmethane), a phenolic compound and a major component of curcuma species, used for imparting colour and flavour to food, possesses antiinflammatory (Satoskar et al 1986;Surh et al 2001), antioxidant properties (Sharma 1976;Araujo & Leon 2001) and afford protection against chemical carcinogen-induced tumourigenesis in skin, colon, forestomach, duodenal, lung and prostate cancer in animal bioassay systems (Azuine & Bhide 1992;Huang et al 1992Huang et al & 1993Dorai et al 2001;Smith et al 2001;Mori et al 2001). Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agents and chemical trials using it have been carried out (Li & Lin-Shia 2001).…”

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confidence: 99%

“…Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agents and chemical trials using it have been carried out (Li & Lin-Shia 2001). Some studies suggest that the antiinflammatory and antioxidant properties of curcumin (Sharma 1976;Satoskar et al 1986;Araujo & Leon 2001), besides its protective effect against tumour promoter-caused induction of ornithine decarboxylase (Huang et al 1988) play an important role against carcinogen-induced development of neoplasia (Huang et al 1988;Wattenberg 1992), and is an inhibitor of reactive oxygen species-generating enzymes such as lipooxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase (Huang et al 1991;Goel et al 2001;Surh et al 2001). Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and I kappa B kinase .…”

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confidence: 99%

“…In addition, curcumin inhibits the expression of c-fos, c-myc and c-jun (Kakar & Roy 1994;Limtrakul et al 2001) and induces apoptosis (Piwocka et al 2001). Despite the fact that 1) curcumin and its derivatives have shown a significant protection against tumourigenesis in several animal tumour bioassay systems (Sharma 1976;Satoskar et al 1986;Huang et al 1992;Goel et al 2001;Mori et al 2001Surh et al 2001 2) depletion in the activities of antioxidant and phase II enzymes occur during tumourigenesis (Perchellet & Perchellet 1989;Sun 1990) 3) cancer chemopreventive agents enhances the activity of these enzymes in target tissues (Wattenberg & Loccia 1990). Since it is capable of inhibiting various kinds of injuries and neoplasm particularly those, which are mediated through the generation of reactive oxygen species.…”

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confidence: 99%

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Dietary Supplementation of Curcumin Enhances Antioxidant and Phase II Metabolizing Enzymes in ddY Male Mice: Possible Role in Protection against Chemical Carcinogenesis and Toxicity

Iqbal

Sharma

Okazaki

et al. 2003

Pharmacology & Toxicology

272

147

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Dietary antioxidants protect laboratory animals against the induction of tumours by a variety of chemical carcinogens. Among possible mechanism of protection against chemical carcinogenesis could be mediated via-antioxidantdependent induction of detoxifying enzymes. Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and is commonly used as a spice and food colouring material and exhibits antiinflammatory, antitumour, and antioxidant properties. In this study we therefore investigated the effect of dietary supplementation of curcumin on the activities of antioxidant and phase II-metabolizing enzymes involved in detoxification, and production of reactive oxygen species were quantified in ddY male mice. Dietary supplementation of curcumin (2%, w/v) to male ddY mice for 30 days significantly increased the activities of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and catalase to 189%, 179%, 189%, and 181% in liver and 143%, 134%, 167% and 115% in kidney respectively as compared with corresponding normal diet fed control (PϽ0.05-0.001). Parallel to these changes, curcumin feeding to mice also resulted in a considerable enhancement in the activity of phase II-metabolizing enzymes viz. glutathione S-transferase and quinone reductase to 1.7 and 1.8 times in liver and 1.1 and 1.3 times in kidney respectively as compared with corresponding normal diet fed control (PϽ0.05-0.01). In general, the increase in activities of antioxidant and phase II-metabolizing enzymes was more pronounced in liver as compared to kidney. The induction of such detoxifying enzymes by curcumin suggest the potential value of this compound as protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of curcumin against the induction of tumours in various target organs.

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Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-κB activation

Cited by 1,479 publications

References 250 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

Dietary Supplementation of Curcumin Enhances Antioxidant and Phase II Metabolizing Enzymes in ddY Male Mice: Possible Role in Protection against Chemical Carcinogenesis and Toxicity

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