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Effects of perillyl alcohol on melanoma in the TPras mouse model
Maria Lluria-Prevatt1, Jeanne Morreale, Jacie Gregus
1Stanford University, Department of Radiation Oncology, Stanford, California 94305, USA.
Abstract:
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.
Insights
Topical perillyl alcohol (POH) application delayed tumor onset and reduced melanoma incidence in mice by inhibiting the Ras pathway. POH also decreased Ras protein and downstream signaling in melanoma cells.
Area of Science:
- Oncology
- Dermatology
- Chemoprevention
Background:
- The Ras signaling pathway is crucial for melanoma development and maintenance.
- Perillyl alcohol (POH), a natural monoterpene, inhibits Ras isoprenylation.
- Targeting the Ras pathway offers a potential strategy for melanoma chemoprevention.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of topically applied perillyl alcohol (POH) against melanoma development.
- To investigate the impact of POH on the Ras signaling pathway in a TPras transgenic mouse model.
Main Methods:
- TPras transgenic mice were treated topically with POH (10 mM) before and during carcinogen exposure (dimethylbenz[a]anthracene).
- Tumor incidence and latency were monitored over 38 weeks.
- In vitro studies assessed POH's effects on Ras protein levels, downstream signaling (MAPK, Akt), apoptosis, and reactive oxygen species (ROS).
Main Results:
- Topical POH application delayed tumor appearance and reduced melanoma incidence by 25-35%.
- In vitro, POH decreased Ras protein levels and inhibited MAPK and Akt activation.
- POH pretreatment reduced UV-induced reactive oxygen species but minimally induced apoptosis.
Conclusions:
- Perillyl alcohol (POH) demonstrates chemopreventive potential against melanoma by inhibiting the Ras signaling pathway.
- Targeting Ras via topical POH may be a viable strategy for melanoma prevention.
- POH's antioxidant properties and inhibition of Ras signaling contribute to its anti-melanoma effects.