Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice

Akira Murakami, Takuji Tanaka, Ji Yoon Lee, Young Joon Surh, Ha Won Kim, Kyuichi Kawabata, Yoshimasa Nakamura, Suratwadee Jiwajinda, Hajime Ohigashi

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 μmol) 24 hr before application of dimethylbenz[a]anthracene (0.2 μmol) markedly suppressed tumor incidence by 60% and the number of tumors by 80% per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83% as well as their diameter by 57%. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 μmol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-PI and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome P450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29% to 86%, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.

Original languageEnglish (US)
Pages (from-to)481-490
Number of pages10
JournalInternational Journal of Cancer
Volume110
Issue number4
DOIs
StatePublished - Jul 1 2004

Fingerprint

Ginger
Inbred ICR Mouse
Sesquiterpenes
Skin
Neoplasms
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Proliferating Cell Nuclear Antigen
Tetradecanoylphorbol Acetate
Cyclooxygenase 2
Tumor Biomarkers
Glutathione Transferase
Reverse Transcriptase Polymerase Chain Reaction
Epidermis
NAD
Colonic Neoplasms
Cytochrome P-450 Enzyme System
Hydrogen Peroxide
Superoxide Dismutase
Edema

Keywords

  • 12-O-tetradecanoylphorbol-13-acetate
  • 7,12-dimethylbenz[a]anthracene
  • Cyclooxygense-2
  • Oxidative stress
  • Xenobiotic enzyme
  • Zerumbone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. / Murakami, Akira; Tanaka, Takuji; Lee, Ji Yoon; Surh, Young Joon; Kim, Ha Won; Kawabata, Kyuichi; Nakamura, Yoshimasa; Jiwajinda, Suratwadee; Ohigashi, Hajime.

In: International Journal of Cancer, Vol. 110, No. 4, 01.07.2004, p. 481-490.

Research output: Contribution to journalArticle

Murakami, A, Tanaka, T, Lee, JY, Surh, YJ, Kim, HW, Kawabata, K, Nakamura, Y, Jiwajinda, S & Ohigashi, H 2004, 'Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice', International Journal of Cancer, vol. 110, no. 4, pp. 481-490. https://doi.org/10.1002/ijc.20175
Murakami, Akira ; Tanaka, Takuji ; Lee, Ji Yoon ; Surh, Young Joon ; Kim, Ha Won ; Kawabata, Kyuichi ; Nakamura, Yoshimasa ; Jiwajinda, Suratwadee ; Ohigashi, Hajime. / Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice. In: International Journal of Cancer. 2004 ; Vol. 110, No. 4. pp. 481-490.
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abstract = "We recently showed that zerumbone, a sesquiterpene found in subtropical ginger, suppresses colonic tumor marker formation in rats and induces apoptosis in colon cancer cell lines. In our present study, the anti-tumor initiating and promoting activities of zerumbone in mouse skin were evaluated using a conventional 2-stage carcinogenesis model. A single topical pretreatment to mouse skin (2 μmol) 24 hr before application of dimethylbenz[a]anthracene (0.2 μmol) markedly suppressed tumor incidence by 60{\%} and the number of tumors by 80{\%} per mouse. Repeated pretreatment (16 nmol) twice weekly during the post-initiation phase reduced the number of 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol)-induced tumors by 83{\%} as well as their diameter by 57{\%}. Multiple reverse transcriptase (RT) PCR experiments revealed that zerumbone (2 μmol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-PI and NAD(P)H quinone oxidoreductase in the epidermis, but not that of cytochrome P450 1A1 or 1B1. Further, it diminished TPA-induced cyclooxygenase-2 protein expression and phosphorylation of extracellular signal-regulated kinase 1/2, while pretreatment(s), in either the priming or activation stage or both, reduced double TPA application-induced hydrogen peroxide formation and edema induction by 29{\%} to 86{\%}, respectively. Histologic examination revealed that pretreatment(s) with zerumbone suppressed leukocyte infiltration and reduced proliferating cell nuclear antigen-labeling indices. Together, our results indicate that zerumbone is a promising agent for the prevention of both tumor initiating and promoting processes, through induction of anti-oxidative and phase II drug metabolizing enzymes as well as attenuation of proinflammatory signaling pathways.",
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AU - Kim, Ha Won

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