Zerumbone, a sesquiterpene in subtropical ginger, suppresses skin tumor initiation and promotion stages in ICR mice.
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.
Murakami
Akira
A
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan. cancer@kais.kyoto-a.ac.jp
Tanaka
Takuji
T
Lee
Ji-Yoon
JY
Surh
Young-Joon
YJ
Kim
Ha Won
HW
Kawabata
Kyuichi
K
Nakamura
Yoshimasa
Y
Jiwajinda
Suratwadee
S
Ohigashi
Hajime
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases; D012717:Sesquiterpenes / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D012717:Sesquiterpenes; C403304:zerumbone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate