Perillyl alcohol attenuates Ras-ERK signaling to inhibit murine skin inflammation and tumorigenesis.
In the present study, the chemopreventive effect of topical application of perillyl alcohol (POH) on 9,10-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumorigenesis and its possible mechanisms of action in Swiss albino mice were investigated. We evaluated the effect of pretreatment of POH (6 and 12 mg/kg body weight) on TPA (2 microg/200 microl of acetone)-induced skin edema, hyperplasia, peroxidase damage and modulation in activities of catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione contents. Application of POH 30 min prior to TPA treatment, showed a protective effect in almost all the investigated parameters. Additionally, pretreatment with POH showed a significant inhibition of ornithine decarboxylase (ODC) activity and [(3)H] thymidine incorporation into epidermal DNA. In promotion phase, a significant reduction was found in tumor incidence and tumor burden in mice pretreated with POH (12 mg/kg body weight) with extension of the latency period from 4 to 8 weeks as compared to those treated with TPA alone. POH significantly suppressed the Ras/Raf/ERK pathway and induced apoptosis in Swiss albino mice skin. Our findings suggested that the chemopreventive efficacy of POH is probably due to the inhibition of oxidative stress responses, inhibition of the Ras cell proliferation pathway and induction of apoptosis in murine skin tumor promotion phase.
Chaudhary
Sandeep Chand
SC
Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi 110062, India.
Alam
M Sarwar
MS
Siddiqui
M S
MS
Athar
M
M
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D039821:Monoterpenes / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D039821:Monoterpenes; C032208:perillyl alcohol; D015127:9,10-Dimethyl-1,2-benzanthracene; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate