Carcinogenesis Advance Access published online on March 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh151
© 2004 by Oxford University Press
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MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
1 Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore
* Corresponding author. E-mail: cofshm{at}nus.edu.sg.
Received 1 January 2003
; revised 9 March 2004
; accepted 9 March 2004
Parthenolide (PN) is a major sesquiterpene lactone of feverfew (Tanacetum parthanium) with known anti-inflammatory activity. However, the anti-cancer 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 anti-cancer 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 to 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 anti-cancer effects using cultured JB6 murine epidermal cells. Non-cytotoxic concentrations of PN significantly inhibited UVB-induced AP-1 DNA binding and transcriptional activity. In addition, PN pretreatment also inhibited c-Jun-N-terminal kinase (JNK) and p38 kinase activation. More importantly, we found that impaired AP-1, JNK and p38 signaling lead to the sensitization of JB6 cells to UVB-induced apoptosis. Data from our study for the first time confirm the anti-cancer property of parthenolide in an animal model, and provide evidence that the inhibitory effects on AP-1 and MAPKs serve as one of the underlying mechanisms for the cancer chemopreventive property of PN.
Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms
2 Health Effects Laboratory Division, National Institutes of Occupational Safety and Health, Morgantown, West Virginia 26505, USA
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