Effects of perillyl alcohol on melanoma in the TPras mouse model.
This study evaluates the chemopreventive effects of topically applied perillyl alcohol on the development of melanoma in TPras transgenic mice. Our strategy was to target critical pathways in the development of melanoma, in particular, the ras pathway. Ras has been shown in our experimental mouse model, as well as others, to be important in the development and maintenance of melanomas. Perillyl alcohol (POH), a naturally occurring monoterpene, inhibits the isoprenylation of small G protein, including Ras. POH (10 mM) was applied to the shaved dorsal skin of TPras mice starting 1 week before five treatments of dimethylbenz[a]anthracene (50 microg) and was continued for 38 weeks. We observed a delay in the appearance of tumors and a 25-35% reduction in melanoma incidence. POH treatment of melanoma cells in vitro reduced the levels of detectable Ras protein and inhibits the activation of downstream targets, mitogen-activated protein kinases and Akt. POH only minimally induced apoptosis in this system. Pretreatment but not post-treatment of the melanoma cells with POH, however, markedly reduced levels of UV-induced reactive oxygen species. These studies suggest that POH inhibition of the Ras signaling pathway may be an effective target for chemoprevention of melanoma.
Lluria-Prevatt
Maria
M
Stanford University, Department of Radiation Oncology, Stanford, California 94305, USA.
Morreale
Jeanne
J
Gregus
Jacie
J
Alberts
David S
DS
Kaper
Fiona
F
Giaccia
Amato
A
Powell
Marianne Broome
MB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008545:Melanoma / Q000517:prevention & control* / Q000662:veterinary; D051379:Mice; D008822:Mice, Transgenic; D039821:Monoterpenes; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000517:prevention & control* / Q000662:veterinary; D013729:Terpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D039821:Monoterpenes; D013729:Terpenes; C032208:perillyl alcohol; D018631:ras Proteins