Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice

A. Murakami, Yoshimasa Nakamura, K. Torikai, T. Tanaka, T. Koshiba, K. Koshimizu, S. Kuwahara, Y. Takahashi, K. Ogawa, M. Yano, H. Tokuda, H. Nishino, Y. Mimaki, Y. Sashida, S. Kitanaka, H. Ohigashi

Research output: Contribution to journalArticle

296 Citations (Scopus)

Abstract

The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-γ in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 μmol)TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P <0.001) and 75.7% (P <0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

Original languageEnglish
Pages (from-to)5059-5066
Number of pages8
JournalCancer Research
Volume60
Issue number18
Publication statusPublished - Sep 15 2000
Externally publishedYes

Fingerprint

Citrus
Phorbol Esters
Tetradecanoylphorbol Acetate
Nitric Oxide
Oxidative Stress
Inflammation
Skin
Leukocytes
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Neoplasms
Carcinogenesis
Granulocyte Precursor Cells
Inbred ICR Mouse
Proliferating Cell Nuclear Antigen
Human Development
Dinoprostone
Superoxides
Hydrogen Peroxide
Lipopolysaccharides

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Murakami, A., Nakamura, Y., Torikai, K., Tanaka, T., Koshiba, T., Koshimizu, K., ... Ohigashi, H. (2000). Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice. Cancer Research, 60(18), 5059-5066.

Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice. / Murakami, A.; Nakamura, Yoshimasa; Torikai, K.; Tanaka, T.; Koshiba, T.; Koshimizu, K.; Kuwahara, S.; Takahashi, Y.; Ogawa, K.; Yano, M.; Tokuda, H.; Nishino, H.; Mimaki, Y.; Sashida, Y.; Kitanaka, S.; Ohigashi, H.

In: Cancer Research, Vol. 60, No. 18, 15.09.2000, p. 5059-5066.

Research output: Contribution to journalArticle

Murakami, A, Nakamura, Y, Torikai, K, Tanaka, T, Koshiba, T, Koshimizu, K, Kuwahara, S, Takahashi, Y, Ogawa, K, Yano, M, Tokuda, H, Nishino, H, Mimaki, Y, Sashida, Y, Kitanaka, S & Ohigashi, H 2000, 'Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice', Cancer Research, vol. 60, no. 18, pp. 5059-5066.
Murakami, A. ; Nakamura, Yoshimasa ; Torikai, K. ; Tanaka, T. ; Koshiba, T. ; Koshimizu, K. ; Kuwahara, S. ; Takahashi, Y. ; Ogawa, K. ; Yano, M. ; Tokuda, H. ; Nishino, H. ; Mimaki, Y. ; Sashida, Y. ; Kitanaka, S. ; Ohigashi, H. / Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice. In: Cancer Research. 2000 ; Vol. 60, No. 18. pp. 5059-5066.
@article{207c705162e44b08ae16b611bbde986e,
title = "Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice",
abstract = "The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-γ in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 μmol)TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2{\%} (P <0.001) and 75.7{\%} (P <0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.",
author = "A. Murakami and Yoshimasa Nakamura and K. Torikai and T. Tanaka and T. Koshiba and K. Koshimizu and S. Kuwahara and Y. Takahashi and K. Ogawa and M. Yano and H. Tokuda and H. Nishino and Y. Mimaki and Y. Sashida and S. Kitanaka and H. Ohigashi",
year = "2000",
month = "9",
day = "15",
language = "English",
volume = "60",
pages = "5059--5066",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion mice

AU - Murakami, A.

AU - Nakamura, Yoshimasa

AU - Torikai, K.

AU - Tanaka, T.

AU - Koshiba, T.

AU - Koshimizu, K.

AU - Kuwahara, S.

AU - Takahashi, Y.

AU - Ogawa, K.

AU - Yano, M.

AU - Tokuda, H.

AU - Nishino, H.

AU - Mimaki, Y.

AU - Sashida, Y.

AU - Kitanaka, S.

AU - Ohigashi, H.

PY - 2000/9/15

Y1 - 2000/9/15

N2 - The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-γ in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 μmol)TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P <0.001) and 75.7% (P <0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

AB - The intake of citrus fruits has been suggested as a way to prevent the development of some types of human cancer. Nitric oxide (NO) is closely associated with the processes of epithelial carcinogenesis. We attempted a search for NO generation inhibitors in Citrus unshiu. The active constituent was traced by an activity-guiding separation. NO and superoxide (O2-) generation was induced by a combination of lipopolysaccharide and IFN-γ in mouse macrophage RAW 264.7 cells, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocyte HL-60, respectively. Expression of inducible NO synthase and cyclooxygenase 2 proteins were detected by Western blotting. The in vivo anti-inflammatory and antitumor promoting activities were evaluated by topical TPA application to ICR mouse skin with measurement of edema formation, epidermal thickness, leukocyte infiltration, hydrogen peroxide production, and the rate of proliferating cell nuclear antigen-stained cells. As a result, nobiletin, a polymethoxyflavonoid, was identified as an inhibitor of both NO and O2- generation. Nobiletin significantly inhibited two distinct stages of skin inflammation induced by double TPA application [first stage priming (leukocyte infiltration) and second stage activation (oxidative insult by leukocytes)] by decreasing the inflammatory parameters. It also suppressed the expression of cyclooxygenase-2 and inducible NO synthase proteins and prostaglandin E2 release. Nobiletin inhibited dimethylbenz[a]anthracene (0.19 μmol)TPA (1.6 nmol)-induced skin tumor formation at doses of 160 and 320 nmol by reducing the number of tumors per mouse by 61.2% (P <0.001) and 75.7% (P <0.001), respectively. The present study suggests that nobiletin is a functionally novel and possible chemopreventive agent in inflammation-associated tumorigenesis.

UR - http://www.scopus.com/inward/record.url?scp=0034665123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034665123&partnerID=8YFLogxK

M3 - Article

C2 - 11016629

AN - SCOPUS:0034665123

VL - 60

SP - 5059

EP - 5066

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 18

ER -