title: Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms.
abstract: Parthenolide (PN) is a major sesquiterpene lactone of feverfew (Tanacetum parthanium) with known anti-inflammatory activity. However, the anticancer effects of PN have not been well studied. In the present investigation, we examined the cancer chemopreventive property of PN using a combination of in vivo and in vitro approaches. We first tested the anticancer effect of PN in UVB-induced skin cancer model. Mice fed with PN (1 mg/day) showed a delayed onset of papilloma incidence, a significant reduction in papilloma multiplicity (papilloma/mouse) and sizes when compared with the UVB-only group. To our surprise, neither PN nor the known cyclooxygenase (COX)-2 inhibitor celecoxib inhibit UVB-induced COX-2 expression and epidermal prostaglandin E2 (PGE2) production. We next investigated the molecular mechanism(s) involved in its anticancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic concentrations of PN significantly inhibited UVB-induced activator protein-1 DNA binding and transcriptional activity. In addition, PN pre-treatment also inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More importantly, we found that impaired AP-1, JNK and p38 signaling led to the sensitization of JB6 cells to UVB-induced apoptosis. Data from our study for the first time confirm the anticancer property of PN in an animal model, and provide evidence that the inhibitory effects on AP-1 and mitogen-activated protein kinases serve as one of the underlying mechanisms for the cancer chemopreventive property of PN.
authors.affiliation: Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore.
authors.forename: Yen-Kim
authors.initials: YK
authors.lastname: Won
authors.forename: Choon-Nam
authors.initials: CN
authors.lastname: Ong
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D000068579:Celecoxib; D016923:Cell Death; D051546:Cyclooxygenase 2; D004247:DNA / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D005260:Female; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D051379:Mice; D008812:Mice, Hairless; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008956:Models, Chemical; D009381:Neoplasms, Radiation-Induced / Q000517:prevention & control*; D010212:Papilloma / Q000517:prevention & control; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases; D011485:Protein Binding; D011720:Pyrazoles; D012717:Sesquiterpenes / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000209:etiology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D012717:Sesquiterpenes; D013449:Sulfonamides; D018808:Transcription Factor AP-1; C002669:parthenolide; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib; D015232:Dinoprostone