Sang Sup Lee

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

A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.

Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a primary pungent and irritating principle present in chilies and red peppers which are widely used as spices. Because of its selective effects on the functions of a defined subpopulation of sensory neurons, capsaicin is currently used as a versatile tool for the study of pain mechanisms and also for pharmacotherapy to treat several pain disorders. Considering the frequent consumption of capsaicin as a food additive and its current medicinal use, correct assessment of hazardous effects of this compound is important. Mutagenic and carcinogenic activities of capsaicin and chili extracts have been studied, but results are conflicting. Mammalian metabolism of capsaicin has been also reported. Capsaicin appears to interact with xenobiotic metabolizing enzymes, particularly microsomal cytochrome P450-dependent monooxygenases which are involved in activation as well as detoxification of various chemical carcinogens and mutagens. Recent studies have shown that hepatic cytochrome P450 2E1 catalyzes the conversion of capsaicin to reactive species such as the phenoxy radical intermediate capable of covalently binding to the active site of the enzyme as well as tissue macromolecules. While covalent modification of protein and nucleic acids leads to toxicity including necrosis, mutagenesis, and carcinogenesis, suicidal inhibition of microsomal cytochrome P450 may prohibit further activation of capsaicin and also of other toxic xenobiotics. Results from recent studies indicate that capsaicin possesses the chemoprotective activity against some chemical carcinogens and mutagens.

Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice

A wide array of phytochemicals have been shown to possess potential cancer chemopreventive properties. Ginger contains pungent phenolic substances with pronounced antioxidative and antiinflammatory activities. In the present study, we have determined the antitumor promotional activity of [6]-gingerol, a major pungent principle of ginger, using a two-stage mouse skin carcinogenesis model. Topical application of [6]-gingerol onto shaven backs of female ICR mice prior to each topical dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly inhibited 7,12-dimethylbenz[a]anthracene-induced skin papillomagenesis. The compound also suppressed TPA-induced epidermal ornithine decarboxylase activity and inflammation.

Capsaicin suppresses phorbol ester-induced activation of NF-κB/Rel and AP-1 transcription factors in mouse epidermis

Capsaicin, the principal pungent ingredient of hot chili peppers, has anti-inflammatory and analgesic properties and is currently used as a topical cream for the management of various neuropathic conditions. In the present study, topical application of capsaicin onto dorsal skin of female ICR mice strongly suppressed phorbol ester-stimulated activation of NF-kappaB via blockade of IkappaB-alpha degradation with subsequent inhibition of nuclear translocation of the functionally active NF-kappaB subunit, p65. Likewise, phorbol ester-induced activation of activator protein-1 (AP-1) was abolished by capsaicin pretreatment. Since altered transactivation of NF-kappaB and AP-1 has been implicated for neoplastic transformation and progression, the suppression of these transcription factors by capsaicin may account for its previously reported chemopreventive effects on mouse skin tumorigenesis as well as inflammation.

Inhibition of Phorbol Ester–Induced COX-2 Expression by Epigallocatechin Gallate in Mouse Skin and Cultured Human Mammary Epithelial Cells

Green tea polyphenols are reported to possess substantial antiinflammatory and chemopreventive properties. However, the molecular mechanism of chemopreventive activity of green tea polyphenols is not fully understood. An abnormally elevated level of cyclooxygenase-2 (COX-2) is implicated in the pathogenesis of carcinogenesis. In the present study, we found that pretreatment of the green tea extract enriched with catechin and epigallocatechin gallate (EGCG) by gavage inhibited COX-2 expression induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse skin. Similarly, EGCG downregulated COX-2 in TPA-stimulated human mammary epithelial cells (MCF-10A) in culture. To further elucidate the underlying mechanism of COX-2 inhibition by green tea extract and EGCG, we examined their effects on the activation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), which are upstream enzymes known to regulate COX-2 expression in many cell types. Pretreatment with EGCG as well as green tea extract caused a decrease in the activation of ERK. In addition, EGCG inhibited the catalytic activity of ERK and p38 MAPK, suggesting that these signal-transducing enzymes could be potential targets for previously reported antitumor promoting activity of EGCG.

Antioxidative and antitumor promoting effects of [6]-paradol and its homologs

Recently, considerable attention is focused on anti-carcinogenic phytochemicals, particularly those derived from medicinal or edible plants. [6]-Paradol, a pungent phenolic compound present in certain Zingiberaceae plants, is known to have antimicrobial and analgesic activities. The compound has been reported to attenuate promotion of skin carcinogenesis and TPA-induced ear edema in female ICR mice, and to induce apoptosis in cultured human promyelocytic leukemia (HL-60) cells. In this study, we performed several biochemical studies to evaluate and compare the cancer chemopreventive potential of [6]-paradol and its synthetic derivatives. [6]-Paradol and its synthetic nonpungent analog, [6]-dehydroparadol significantly decreased the incidence and the multiplicity of skin tumors initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of [6]-paradol and its derivatives inhibited TPA-induced ear edema and H(2)O(2) production and myeloperoxidase activity in the dorsal skin of mice. Induction of TPA-induced mouse epidermal ornithine decarboxylase (ODC) activity and H(2)O(2)- and UV-induced formation of oxidized DNA bases in vitro were also attenuated by the above compounds. These results indicate that [6]-paradol and its derivatives possess the cancer chemopreventive potential.

Metabolism of capsaicinoids: Evidence for aliphatic hydroxylation and its pharmacological implications

A new metabolic oxidation pathway of capsaicin (N-[(4-hydroxy-3-methoxyphenyl)-methyl]-8-methyl-(E)-6 -nonenamide), a major pungent and pharmacologically active principle of hot peppers, was investigated. Incubation of capsaicin with phenobarbital-induced rat liver postmitochondrial supernatant enriched with NADPH-generating system produced N-(4,5-dihydroxy-3-methoxybenzyl)-(E)-6 -nonenylamide and a more polar metabolite. The latter metabolite was spectrophotometrically and chromatographically identical to authentic omega-hydroxycapsaicin. This new metabolite was also detected in the urine of rabbits given capsaicin by gastric intubation. Other analogs of capsaicin, such as dihydrocapsaicin and nonivamide, also formed similar metabolites via aliphatic hydroxylation. When tested for antinociceptive activity as well as pungency, the above polar metabolites were found to be inactive while their parent compounds exhibited strong sensory effects. Capsaicin interacted irreversibly with heptic drug metabolizing enzymes, thereby inhibiting their activity as indicated by prolongation of pentobarbital sleeping time in rats. Such inhibition of drug metabolism was not observed with omega-hydroxycapsaicin. These findings suggest that metabolism of capsaicinoids via hydroxylation of their side chains plays an important role in the detoxification of these pharmacologically active substances.