Abstract
Activated macrophages express inducible isoforms of nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), and produce excessive amounts of nitric oxide (NO) and prostaglandin E2 (PGE2), which play key roles in the processes of inflammation and carcinogenesis. The root ofPaeonia lactiflora Pall., and the root cortex ofPaeonia suffruticosa Andr., are important Chinese crude drugs used in many traditional prescriptions. 1,2,3,4,6-penta-O-galloyl-β-D-glu-cose (PGG) is a major bioactive constituent of both crude drugs. PGG has been shown to possess potent anti-oxidant, anti-mutagenic, anti-proliferative and anti-invasive effects. In this study, we examined the inhibitory effects of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) isolated from the root ofPaeonia lactiflora Pall, on the COX-2 and iNOS activity in LPS-activated Raw 264.7 cells, COX-1 in HEL cells. To investigate the structure-activity relationships of gal-late and gallic acid for the inhibition of iNOS and COX-2 activity, we also examined (-)-epigal-locatechin gallate (EGCG), gallic acid, and gallacetophenone. The results of the present study indicated that PGG, EGCG, and gallacetophenone treatment except gallic acid significantly inhibited LPS-induced NO production in LPS-activated macrophages. All of the four compounds significantly inhibited COX-2 activity in LPS-activated macrophages. Among the four compounds examined, PGG revealed the most potent in both iNOS (IC50 ≈ 18 μg/mL) and COX-2 inhibitory activity (PGE2: IC50 ≈ 8 μg/mL and PGD2: IC50 ≈ 12 μg/mL), respectively. Although further studies are needed to elucidate the molecular mechanisms and structure-activity relationship by which PGG exerts its inhibitory actions, our results suggest that PGG might be a candidate for developing anti-inflammatory and cancer chemopreventive agents.
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Alice, H. L., Michael, J. B., and Robert, R. G., Regulation of prostaglandin H systhase mRNA levels and prostaglandin biosynthesis by platelet-derived growth factor.J. Biol. Chem., 264, 17379–17383 (1989).
Amiram, R., Angela, W., Ned, S., and Philip, N., Regulation of fibroblast cyclooxygenase synthesis by interleukin-1.J. Bio. Chem., 263, 3022–3024 (1988).
Berg, J., Christoph, T., Widerna, M., and Bodenteich, A., Isoenzyme-specific cyclooxygenase inhibitors: A whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell lin-Mono Mac 6.J. Pharmacol. Toxicol. Methods, 37, 179–186 (1997).
Bhimani, R. S., Troll, W., Grunberger, D., and Frenkel, K., Inhibition of oxidative stress in HeLa cells by chemopreventive agents.Can. Res., 53, 4528–4533 (1993).
Cao, Y. and Prescott, S. M., Many actions of cyclooxygenase-2 in cellular dynamics and cancer.J. Cell Physiol., 190, 279–286 (2002).
Chen, Y. C., Liang, Y. C., Lin-Shiau, S. Y., Ho, C. Y., and Lin, J. K., Inhibition of TPA-induced PKC and AP-1 binding activities by Theaflavin-3,3′-digallate from black tea in NIH3T3 cells.J. Agric. Food Chem., 367, 379–388 (1999).
Chin, K., Kurashima, Y., Ogura, T., Tajiri, H., Yoshida, S., and Esumi, H., Induction of vascular endothelial growth factor by nitric oxide in human glioblastoma and hepatocellular carcinoma cells.Oncogene, 15, 437–442 (1997).
Dean, A. K., Bradley, S. R., Brian, C. V., Robert, W. L., and Harvey, R. H., TIS 10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.J. Biol. Chem., 266, 12866–12872 (1991).
Fujiki, H., Yoshizawa, S., Horiuchi, T., Suganuma, M., Yatsunami, J., Nishiwaki, S., Okabe, S., Nishiwaki-Matsushima, R., Okuda, T., and Sugimura, T., Anticarcinogenic effects of (-)-epigallocatechin gallate.Prev. Med., 21, 503–509 (1992).
Funk, C. D., Prostaglandins and leukotrienes: advances in eicosanoid biology.Science, 294 (5548), 1871–1875 (2001).
Hawkey, C. J., COX-2 inhibitors.Lancer, 353, 307–314 (1999).
Ho, C. T., Chen, Q., Shi, H., Zhang, K. Q., and Rosen, R. T., Antioxidative effect of polyphenol extract prepared from various Chinese teas.Prev. Med., 21, 520–525 (1992).
Ho., L.-L., Chen, W.-J., Lin-Shiau, S.-Y., and Lin, J.-K., Penta-O-galloyl-beta-D-glucose inhibits the invasion of mouse melanoma by suppressing metalloproteinase-9 through down-regulation of activator protein-1.Eur. J. Pharmacol., 453, 149–158 (2002).
Inoue, M., Suzuki, R., Koide, T., Sakaguchi, N., Ogihara, Y., and Yabu, Y. Antioxidant, gallic acid, induces apoptosis in HL-60RG cells.Biochem. Biophys. Res. Commun., 204, 898–904 (1994)
Jenkins, D. C., Charles, I. G., Thomsen, L. L., Moss, D. W., Holmes, L. S., Baylis, S. A., Rhodes, P., Westmore, K., Emson P. C., and Moncada, S., Roles of nitric oxide in tumor growth.Proc. Natl. Acad. Sci., USA, 92, 4392–4396 (1995).
Katiyar, S. K., Agarwal, R., Zaim, M. T., and Mukhtar, H., Protection againstN-nitrosodiethylamine and benzo(α)pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea.Carcinogenesis, 14, 849–855 (1993).
Leahy, K. M., Ornberg, R. L., Wang, Y., Zwifel, B. S., Koki, A. T., and Masferrer, J. L., Cyclooxygenase-2 inhibition by celecoxib, reduces proliferation and induces apoptosis in angiogenic endothelial cellsin vivo.Cancer Res., 62, 625–631 (2002).
Liang, Y C., Chen, Y C., Lin, Y L., Lin-Shiau, S. Y., Ho, C. T., and Lin, J. K., Suppression of extracellular signals and cell proliferation by the black tea polyphenol, theaflavin-3,3′-digallate.Carcinogenesis, 20, 733–736 (1999).
Lin, Y. L., Juan, I. M., Chen, Y. L., Liang, Y. C., and Lin, J. K., Composition of polyphenols in fresh tea leaves and associations of their oxygen-radical-absorbing capacity with anti-proliferative actions in fibroblast cells.J. Agric. Food Chem., 44, 1387–1394 (1996).
Lin, Y. L. and Lin J. K., (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kB.Mol. Pharmacol., 52, 465–472 (1997).
Liu, R. H. and Hotchkiss, J. H., Potential genotoxicity of chronically elevated nitric oxide: A review.Mutat. Res., 339, 73–89 (1995).
Marietta, M. A., Nitric oxide synthase structure and mechanism.J. Biol. Chem., 268, 12231–12234 (1993).
Miyamoto, K., Kishi, N., Koshiura, R., Yoshida, T., Hatano, T., and Okuda, T., Relationship between the structures and the antitumor activities of tannins.Chem. Pharm. Bull., 35, 814–822 (1987).
Morbidelli, L., Chang, C. H., Douglas, J. G., Granger, H. J., Ledda, F., and Ziche, M., Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium.Am. J. Physiol., 270, H411-H415 (1996).
Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.J. Immunol. Methods, 65, 55–63 (1983).
Oh, G.-S., Pae, H.-O., Ph, H., Hong, S.-G., Kim, I.-K., Chai, K-Y., Yun, Y.-G., Kwon, T.-O., and Chung, H.-T.,In vitro antiproliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells.Cancer Lett., 174, 17–24 (2001).
Ono, K., Sawada, T., Murata, Y., Saito, E., Iwasaki, A., Arakawa, Y., Kurokawa, K., and Hashimoto, Y., Pentagalloylglucose, an antisecretory component of Paeoniae radix, inhibits gastric H+, K+-ATPase.Clinica. Chimica. Acta, 290, 159–167 (2000).
O’Sullivan, M. G., Huggins Jr., E. M., Meade, E. A., DeWitt, D. L., and McCall, C. E., Lipopolysaccharide induces prostaglandin H synthase-2 in alveolar macrophages.Biochem. Biophys. Res. Commun., 187, 1123–1127 (1992).
Pan, M.-H., Lin, J.-H., Lin-Shiau S.-Y and Lin, J.-K., Induction of apoptosis by penta-O-galloyl-beta-D-glucose through activation of caspase-3 in human leukemia HL-60 cells.Eur. J. Pharmacol., 381, 171–183 (1999).
Sachs, G., Chang, H. H., Ravon, E., Schckman, R., Lewin, M., and Saccomani, G. A., Non electrogenic H+ pump in plasma membranes of hog stomach.J. Biol. Chem., 261, 16788–16791 (1976).
Satoh, K., Nagai, F., Ushiyama, K., Yasuda, I, Seto, T., and Kano, I., Inhibition of Na+, K(+)-ATPase by 1,2,3,4,6-penta-O-galloyl-beta-D-glucose, a major constituent of both moutan cortex and Paeoniae radix.Biochem. Parmacol., 53, 611–614 (1997).
Schlodorff, D., Renal complications of nonsteroidal anti-inflammatory drugs.Kidney Int., 44, 643–653 (1993).
Schmidt, H. H. and Walter, U., NO at work.Cell, 78, 919–925 (1994).
Simon, L. S., Role of regulation of cyclooxygenase-2 during inflammation.Am. J. Med., 106, 37S-42S. (1999).
Subbaramaiah, K., Telang, N., Ramonetti, J. T., Araki, R., Devito, B., Weksker, B. B., and Dannenberg, A. J., Transcription of cyclooxygenase-2 is enhanced in transformed mammary epithelial cells.Cancer Res., 56, 4424–4429 (1996).
Szabo, C., Alterations in nitric oxide production in various forms of circulatory shock.New Hortz., 3, 2–32 (1995).
Tsujii, M., Kawano S., and DuBois, R. N., Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential.Proc. Natl. Acad. Sci. USA., 94, 3336–3340 (1997).
Tsujii, M., Kawano, S., Tsuji, S., Sawaoka, H., Hori, M., and DuBois, R. N., Cyclooxygenase regulates angiogenesis induced by colon cancer cells.Cell, 93, 705–716 (1998).
Tunctan, B., Uludag, O., Altug, S., and Abacioglu, N., Effects of nitric oxide synthase inhibition in lipopolysaccharide-induced sepsis in mice.Pharmacol. Res., 38, 405–411 (1998).
Vane, J. R., Bakhle, Y S., and Botting, R. M., Cyclooxygenases 1 and 2.Annu. Rev. Pharmacol. Toxicol., 38, 97–120 (1998).
Xie, W. Q., Kashiwabara, Y., and Nathan, C., Role of transcription factor NFkB/Rel in induction of nitric oxide synthase.J. Biol. Chem., 269, 4705–4708 (1994).
Ziche, M., Morbidelli, L., Masini, E., Amerini, S., Granger, H. J., Maggi, C. A., Geppetti P., and Ledda, F., Nitric oxide mediates angiogenesisin vivo and endothelial cell growth and migrationin vivo promoted by substance P.J. Clin. Invest., 94, 2036–2044 (1994).
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Lee, SJ., Lee, IS. & Mar, W. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 activity by 1,2,3,4,6-Penta-O-galloyl-β-D-glucose in murine macrophage cells. Arch Pharm Res 26, 832–839 (2003). https://doi.org/10.1007/BF02980029
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DOI: https://doi.org/10.1007/BF02980029