Chemopreventive effect of farnesol on DMBA/TPA-induced skin tumorigenesis: involvement of inflammation, Ras-ERK pathway and apoptosis.
OBJECTIVE
Naturally-derived farnesol has been reported for its chemopreventive and chemotherapeutic efficacy in various cancers. However, the mechanism of action of farnesol is still to be elucidated. The present study demonstrates the chemopreventive potential of farnesol on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis in Swiss albino mice.


METHODS
Farnesol at three different doses 25, 50 and 100 mg/kg body weight was topically applied to the mouse skin, 30 min prior to TPA (2 microg/200 microl acetone) to evaluate edema, hyperplasia, expression of cyclooxygenase-2 (COX-2), oxidative stress response and hyperproliferation, and expression of Ras, Raf, p-ERK1/2, Bax and Bcl-2 in DMBA/TPA-induced tumors.


RESULTS
Farnesol at both the low doses significantly reduced the TPA-induced skin edema, hyperplasia, expression of COX-2 and oxidative stress response. Interestingly, higher dose of farnesol did not show any significant response. Pretreatment of farnesol significantly decreased TPA-induced ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation in dose-dependent manner. During promotion phase, farnesol with higher dose significantly regressed tumor incidence and tumor burden with an extension of latency period of 4-8 weeks. More importantly, low doses of farnesol significantly inhibited Ras/Raf/ERK1/2 signaling pathway in mouse skin tumors whereas higher dose of farnesol induced the pathway. Moreover, farnesol at all doses altered Bax/Bcl-2 ratio which leads to induction of apoptosis as confirmed by DNA fragmentation.


CONCLUSIONS
These findings revealed that oxidative stress, inflammation, Ras/Raf/ERK1/2 pathway and apoptosis collectively played a crucial role in the chemopreventive activity of farnesol to inhibit the murine skin tumorigenesis.
Chaudhary
Sandeep Chand
SC
Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi-110062, India. sandeepcchaudhary@rediffmail.com
Alam
Mohammad Sarwar
MS
Siddiqui
Mohammad Saeed
MS
Athar
Mohammad
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018890:Chemoprevention; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005204:Farnesol / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D018631:ras Proteins / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D005204:Farnesol; D015127:9,10-Dimethyl-1,2-benzanthracene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate