Chemopreventive effect of farnesol on DMBA/TPA-induced skin tumorigenesis: involvement of inflammation, Ras-ERK pathway and apoptosis.

Abstract:

AIMS: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. MAIN 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. KEY FINDINGS: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. SIGNIFICANCE: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.

journal_name

Life Sci

journal_title

Life sciences

authors

Chaudhary SC,Alam MS,Siddiqui MS,Athar M

doi

10.1016/j.lfs.2009.05.008

subject

Has Abstract

pub_date

2009-07-31 00:00:00

pages

196-205

issue

5-6

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(09)00226-4

journal_volume

85

pub_type

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