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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Apr;89(4):361–370. doi: 10.1111/j.1349-7006.1998.tb00572.x

Inhibitory Effects of Curcumin and Tetrahydrocurcuminoids on the Tumor Promoter‐induced Reactive Oxygen Species Generation in Leukocytes in vitro and in vivo

Yoshimasa Nakamura 1, Yoshimi Ohto 1, Akira Murakami 2, Toshihiko Osawa 3, Hajime Ohigashi 1,✉
PMCID: PMC5921825  PMID: 9617340

Abstract

The inhibitory effects of curcumin and two tetrahydrocurcuminoids on tumor promoter‐induced oxidative stress in vitro and in vivo were investigated. Curcumin, tetrahydrocurcumin (THC) and dihydroxytetrahydrocurcumin (DHTHC) exhibited significant inhibitory effects on 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced O2‐generation in differentiated HL‐60 cells. The inhibitory activity of THC was weaker than that of curcumin. This tendency was the inverse of the results of previous studies on in vitro antioxidative activity against lipid peroxidation. The curcuminoids inhibited TPA‐induced intracellular peroxide formation in differentiated HL‐60 cells. THC exhibited much weaker inhibition of intracellular peroxide formation than curcumin, suggesting that this inhibition might be attributable to the inhibition of O2‐generation. The inhibitory effects of curcuminoids on TPA‐induced H2O2 formation in female ICR mouse skin were further examined using the double‐TPA‐application model. Each TPA application induces two distinct biochemical events, 1) recruitment of inflammatory cells to the inflammatory regions and 2) activation of oxidant‐producing cells. Double pretreatment of mice with curcuminoids before each TPA treatment significantly suppressed double TPA application‐induced H2O2 formation in the mouse skin. Coadministrations of curcumin with either first or second TPA treatment significantly inhibited H2O2 formation. In addition, THC tends to show weaker inhibitory activities than curcumin in bioassays related to tumor promotion, i.e., inhibition of tumor promoter‐induced inflammation in mouse skin and Epstein‐Barr virus activation. These tendencies were parallel to those in the tumor‐suppressive potential of curcumin and THC in mouse skin, as previously reported. Thus, we concluded that curcuminoids significantly suppress TPA‐induced oxidative stress via both interference with infiltration of leukocytes into the inflammatory regions and inhibition of their activation.

Keywords: Curcumin, Tetrahydrocurcumin, Reactive oxygen species, Mouse skin, HL‐60

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REFERENCES

  • 1. ) Govindarajan , V. S.Turmeric chemistry, technology and quality . CRC Rev. Food Sci. Nutr. , 12 , 199 – 301 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Huang , M.‐T. , Robertson , F. M. , Lysz , T. , Ferraro , T. , Wang , Z. Y. , Georgiadis , C. A. , Laskin , J. D. and Conney , A. H.Inhibition effects of curcumin on carcinogenesis in mouse epidermis . In “Phenolic Compounds in Food and Their Effects on Health II: Antioxidants and Cancer Prevention, Vol. 2 ,” ed. Huang M.‐T. , Ho C.‐T. and Lee C. Y. , ACS Symposium Series 506 , pp. 338 – 349 ( 1992. ). American Chemical Society; , Washington , DC [Google Scholar]
  • 3. ) Azuine , A. M. and Bhide , S. V.Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice . Nutr. Cancer , 17 , 77 – 83 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Rao , C. V. , Rivenson , A. , Simi , B. and Reddy , B. S.Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound . Cancer Res. , 55 , 259 – 266 ( 1995. ). [PubMed] [Google Scholar]
  • 5. ) Tanaka , T. , Makita , H. , Ohnishi , M. , Hirose , Y. , Wang , A. , Mori , H. , Satoh , K. , Hara , A. and Ogawa , H.Chemoprevention of 4‐nitroquinoline 1‐oxide‐induced oral carcinogenesis by dietary curcumin and hesperidin: comparison with the protective effect of β‐carotene . Cancer Res. , 54 , 4653 – 4659 ( 1994. ). [PubMed] [Google Scholar]
  • 6. ) Nishino , H. , Nishino , A. , Takayasu , J. and Hasegawa , T.Antitumor‐promoting activity of curcumin, a major constituent of the food additive ‘turmeric yellow’ J. Kyoto Pref. Univ. Med. , 96 , 725 – 728 ( 1987. ). [Google Scholar]
  • 7. ) Huang , M.‐T. , Smart , R. C. , Wong , C.‐Q. and Conney , A. H.Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12‐O‐tetradecanoylphorbol‐13‐acetate . Cancer Res. , 48 , 5941 – 5946 ( 1988. ). [PubMed] [Google Scholar]
  • 8. ) Huang , M.‐T. , Wang , Z. Y. , Georgiadis , C. A. , Laskin , J. D. and Conney , A. H.Inhibitory effects of curcumin on tumor initiation by benzo[a]pyrene and 7,12‐dimethylbenz[a]anthracene . Carcinogenesis , 13 , 2183 – 2186 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Huang , M.‐T. , Wei , M. , Lu , Y.‐P. , Chang , R. L. , Fisher , C. , Manchand , P. S. , Newmark , H. L. and Conney , A. H.Effects of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin on 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced tumor promotion . Carcinogenesis , 16 , 2493 – 2497 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Huang , M.‐T. , Wei , M. , Yen , P. , Xie , J.‐G. , Han , J. , Frenkel , K. , Grunberger , D. and Conney , A. H.Inhibitory effects of topical application of low doses of curcumin on 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced tumor promotion and oxidized DNA bases in mouse epidermis . Carcinogenesis ( Oxford ), 18 , 83 – 88 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Huang , M.‐T.Antioxidant and antitumorigenic properties of curcumin . In“Food Factors for Cancer Prevention ,” ed. Ohigashi H. , Osawa T. , Terao J. , Watanabe S. and Yoshikawa T. , pp. 249 – 252 ( 1997. ). Springer; , Tokyo . [Google Scholar]
  • 12. ) Huang , M.‐T. , Lou , Y.‐R. , Ma , W. , Newmark , H. L. , Reujl , K. R. and Conney , A. H.Inhibitory effects of dietary curcumin on forestomach duodenal, and colon carcinogenesis on mice . Cancer Res. , 54 , 5841 – 5847 ( 1994. ). [PubMed] [Google Scholar]
  • 13. ) Huang , M.‐T. , Lysz , T. , Ferraro , T. , Abidi , T. F. , Laskin , J. D. and Conney , A. H.Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis . Cancer Res. , 51 , 813 – 819 ( 1992. ). [PubMed] [Google Scholar]
  • 14. ) Kakar , S. S. and Roy , D.Curcumin inhibits TPA‐induced expression of c‐fos, c‐jun, and c‐myc protooncogene messenger RNAs in mouse skin . Cancer Lett. , 87 , 85 – 89 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Huang , T.‐S. , Lee , S.‐C. and Lin , J.‐K.Suppression of c‐Jun/AP‐1 activation by an inhibitor of tumor promotion in mouse fibroblast calls . Proc. Natl. Acad. Sci. USA , 88 , 5292 – 5296 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Liu , J.‐Y. , Lin , S.‐J. and Lin , J.‐K.Inhibitory effects of curcumin on protein kinase C activity induced by 12‐O‐tetradecanoylphorbol‐13‐acetate in NIH 3T3 cells . Carcinogenesis , 14 , 857 – 861 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Sharma , O. P.Antioxidant activity of curcumin and related compounds . Biochem. Pharmacol. , 25 , 1811 – 1812 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Osawa , T. , Sugiyama , Y. , Inayoshi , M. and Kawakishi , S.Antioxidative activity of tetrahydrocurcuminoids . Biosci. Biotech. Biochem. , 59 , 1609 – 1612 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Sugiyama , Y. , Kawakishi , S. and Osawa , T.Involvement of the β‐diketone moiety in the antioxidative mechanism of tetrahydrocurcuminoids . Biochem. Pharmacol. , 52 , 519 – 525 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Srivastava , R.Inhibition of neutrophil response by curcumin . Agents Actions , 28 , 298 – 303 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Joe , B. and Lokesh , B. R.Role of capsaicin, curcumin and dietary n‐3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages . Biochim. Biophys. Acta , 1224 , 255 – 263 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Perchellet , J. P. , Perchellet , E. M. , Gali , H. U. and Gao , X. M.Oxidative stress and multistage skin carcinogenesis . In“Skin Cancer: Mechanisms and Human Relevance ,” ed. Mukhtar H. , pp. 145 – 180 ( 1995. ). CRC Press; , Boca Raton , FL . [Google Scholar]
  • 23. ) Yoon , H. L. , Marcus , C. B. and Pfeifer , R. W.Induction of superoxide by 12‐O‐tetradecanoylphorbol‐13‐acetate and thapsigargin, a non‐phorbol‐ester‐type tumor promoter, in peritoneal macrophages elicited from SENCAR and B6C3F1 mice: a permissive role for the arachidonic acid cascade in signal transduction . Mol. Carcinog. , 7 , 116 – 125 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Kensler , T. W. , Egner , P. A. , Taffe , B. G. and Trush , M. A.Role of free radicals in tumour promotion and progression . In“Skin Carcinogenesis, Progress in Clinical and Biological Research Vol. 298 ,” ed. Slaga T. J. , Klein‐Szanto A. J. P. , Boutwell R. K. , Stevenson D. E. , Spitzer H. L. and D'Motto B. , pp. 233 – 248 ( 1989. ). Alan R. Liss, Inc; , New York [PubMed] [Google Scholar]
  • 25. ) Wei , H. and Frenkel , K.Suppression of tumor promoter‐induced oxidative events and DNA damage in vivo by sarcophytol A: a possible mechanism of antipromotion . Cancer Res. , 52 , 2298 – 2303 ( 1992. ). [PubMed] [Google Scholar]
  • 26. ) Ji , C. and Marnett , L. J.Oxygen radical‐dependent epoxidation of (7S,8S)‐dihydroxy‐7,8‐dihydrobenzo[a]pyrene in mouse skin in vivo. Stimulation by phorbol esters and inhibition by antiinflammatory steroids . J. Biol. Chem. , 267 , 17842 – 17878 ( 1992. ). [PubMed] [Google Scholar]
  • 27. ) Kensler , T. W. , Egner , P. A. , Moore , K. G. , Taffe , B. G. , Twerdok , L. E. and Trush , M. A.Role of inflammatory cells in the metabolic activation of polycyclic aromatic hydrocarbons in mouse skin . Toxicol. Appl. Pharmacol. , 90 , 337 – 346 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Kim , J. M. , Kim , D. J. , Araki , S. , Iwahori , Y. , Osawa , T. , Murakoshi , M. , Nishino , H. and Tsuda , H.Chemopreventive effect of carotenoids and curcuminoids on mouse colon carcinogenesis induced by 1,2‐dimethylhyrazine . Abstracts of Third National Meeting of Japanese Society for Cancer Prevention , p. 50 ( 1996. ). Nagoya
  • 29. ) Murakami , A. , Ohigashi , H. and Koshimizu , K.Antitumor promotion with food phytochemicals: a strategy for cancer chemoprevention . Biosci. Biotech. Biochem. , 60 , 1 – 8 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Nakayama , T. , Haraguchi , I. , Hashimoto , K. , Sugiyama , Y. and Osawa , T.Suppression of hydrogen peroxide‐induced cytotoxicity toward Chinese hamster lung fibroblasts by chemically modified curcumin . Food Sci. Technol. Int. Tokyo , 3 , 74 – 76 ( 1997. ). [Google Scholar]
  • 31. ) Irie , K. , Hirota , M. , Hagiwara , N. , Koshimizu , K. , Hayashi , H. , Murao , S. , Tokuda , H. and Ito , Y.The Epstein‐Barr virus early antigen inducing indole alkaloids, (–)‐indolactam V and its related compounds, produced by actinomycetes . Agric. Biol. Chem. , 48 , 1269 – 1274 ( 1984. ). [Google Scholar]
  • 32. ) Murakami , A. , Kuki , W. , Takahashi , Y. , Yonei , H. , Nakamura , Y. , Ohto , Y. , Ohigashi , H. and Koshimizu , K.Auraptene, a citrus coumarin, inhibits 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced tumor promotion in ICR mouse skin, possibly through suppression of superoxide generation in leukocytes . Jpn. J. Cancer Res. , 88 , 443 – 452 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. ) Wei , H. , Wei , L. , Frenkel , K. , Bowen , R. and Barnes , S.Inhibition of tumour promoter‐induced hydrogen peroxide formation in vitro and in vivo by genistein . Nutr. Cancer , 20 , 1 – 12 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Murakami , A. , Nakamura , Y. , Koshimizu , K. and Ohigashi , H.Glyceroglycolipids from Citrus hystrix, a traditional herb in Thailand, potently inhibit the tumor promoting activity of 12‐O‐tetradecanoylphorbol‐13‐acetate in mouse skin . J. Agric. Food Chem. , 43 , 2779 – 2783 ( 1995. ). [Google Scholar]
  • 35. ) Murakami , A. , Ohura , S. , Nakamura , Y. , Koshimizu , K. and Ohigashi , H.1′‐Acetoxychavicol acetate, a superoxide anion generation inhibitor, potently inhibits tumor promotion by 12‐O‐tetradecanoylphorbol‐13‐acetate in ICR mouse skin . Oncology , 53 , 386 – 391 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Nakamura , Y. , Murakami , A. , Koshimizu , K. and Ohigashi , H.Inhibitory effects of pheophorbide a, a chlorophyll‐related compound, on skin tumour promotion in ICR mouse skin . Cancer Lett. , 108 , 247 – 255 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Wei , H. and Frenkel , K.Relationship of oxidative events and DNA oxidation in SENCAR mice to in vivo promoting activity of phorbol ester‐type tumor promoters . Carcinogenesis , 14 , 1195 – 1201 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Wei , H. C. , Bowen , R. , Barnes , S. and Wang , Y.Antioxidant and antipromotional effects of the soybean isoflavonoid genistein . Proc. Soc. Exp. Biol. Med. , 208 , 124 – 130 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 39. ) Kunchandy , E. and Rao , M. N. A.Oxygen radical scavenging activity of curcumin . Int. J. Pharm. , 58 , 237 – 240 ( 1990. ). [Google Scholar]
  • 40. ) Cross , A. R. and Jones , O. T. G.Enzymatic mechanisms of superoxide production . Biochim. Biophys. Acta , 1057 , 281 – 298 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 41. ) Henderson , L. M. and Chappell , J. B.NADPH oxidase of neutrophils . Biochim. Biophys. Acta , 1273 , 87 – 107 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 42. ) Curnutte , J. T. , Erickson , R. W. , Ding , J. and Badwey , J. A.Reciprocal interactions between protein kinase C and components of the NADPH oxidase complex may regulate superoxide production by neutrophils stimulated with phorbol ester . J. Biol. Chem. , 269 , 10813 – 10819 ( 1994. ). [PubMed] [Google Scholar]
  • 43. ) Dana , R. , Malech , H. L. and Levy , R.The requirement for phospholipase A2 for activation of the assembled NADPH oxidase in human neutrophils . Biochem. J. , 297 , 217 – 223 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. ) Takeuchi , T. , Nakajima , M. and Morimoto , K.Relationship between the intracellular reactive oxygen species and the induction of oxidative DNA damage in human neutrophil‐like cells . Carcinogenesis , 17 , 1543 – 1548 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 45. ) Reiners , J. J. , Jr. , Pence , B. C. , Barcus , M. C. S. and Cantu , A. R.12‐O‐Tetradecanoylphorbol‐13‐acetate‐dependent induction of xanthine dehydrogenase and conversion to xanthine oxidase in murine epidermis . Cancer Res. , 47 , 1775 – 1779 ( 1987. ). [PubMed] [Google Scholar]
  • 46. ) Wei , H. and Frenkel , K.In vivo formation of oxidized DNA bases in tumor promoter‐treated mouse skin . Cancer Res. , 51 , 4443 – 4449 ( 1991. ). [PubMed] [Google Scholar]
  • 47. ) Ohigashi , H. , Murakami , A. , Nakamura , Y. and Koshimizu , K.Anti‐tumor promoters from edible Thai plants: isolation, cancer preventive potential, and action mechanisms . In“Food Factors for Cancer Prevention ,” ed. Ohigashi H. , Osawa T. , Terao J. , Watanabe S. and Yoshikawa T. , pp. 188 – 193 ( 1997. ). Springer; , Tokyo . [Google Scholar]

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