Carcinogenesis Advance Access originally published online on March 19, 2004
Carcinogenesis 2004 25(8):1449-1458; doi:10.1093/carcin/bgh151
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Carcinogenesis vol.25 no.8 © Oxford University Press 2004; all rights reserved.
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Chemopreventive activity of parthenolide against UVB-induced skin cancer and its mechanisms
1 Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117597, Republic of Singapore and 2 Health Effects Laboratory Division, National Institutes of Occupational Safety and Health, Morgantown, WV 26505, USA
3 To whom the correspondence should be addressed Email: cofshm{at}nus.edu.sg
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.
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