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

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 micromol) 24 hr before application of dimethylbenz[a]anthracene (0.2 micromol) 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 micromol) enhanced the mRNA expression level of manganese superoxide dismutase, glutathione peroxidase-1, glutathione S-transferase-P1 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.

• Authors: Akira Murakami, Takuji Tanaka, Ji-Yoon Lee, Young-Joon Surh, Ha Won Kim, Kyuichi Kawabata, Yoshimasa Nakamura, Suratwadee Jiwajinda, Hajime Ohigashi
• Journal: International journal of cancer (Int J Cancer) Vol. 110 Issue 4 Pg. 481-90 (Jul 01 2004) ISSN: 0020-7136 [Print] United States
• PMID: 15122579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Anticarcinogenic Agents
• Isoenzymes
• Sesquiterpenes
• zerumbone
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• Gstp1 protein, mouse
• Mitogen-Activated Protein Kinases
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Cyclooxygenase 2
• Enzyme Induction (drug effects)
• Female
• Glutathione S-Transferase pi
• Glutathione Transferase (genetics)
• Isoenzymes (antagonists & inhibitors, genetics)
• Mice
• Mice, Inbred ICR
• Mitogen-Activated Protein Kinases (metabolism)
• NAD(P)H Dehydrogenase (Quinone) (genetics)
• Oxidative Stress (drug effects)
• Phosphorylation
• Prostaglandin-Endoperoxide Synthases
• Sesquiterpenes (pharmacology)
• Skin Neoplasms (prevention & control)
• Tetradecanoylphorbol Acetate (pharmacology)