D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.

Abstract

D-Limonene, a common monoterepene has been shown to have antiproliferative, apoptosis-inducing and chemopreventive effects. In the present study, we have investigated the effects of D-limonene on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor development. We found that D-limonene (50 and 100 mg/kg body weight) treatments to the mouse skin significantly reduced the TPA-induced (a) edema and hyperplasia (p < 0.001); (b) expression of cyclooxygenase-2; (c) ornithine decarboxylase activity (p < 0.001); and (d) [(3)H] thymidine incorporation into DNA (p < 0.001). In addition, treatment of D-limonene effectively restored the level of reduced glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, catalase and malondialdehyde production in TPA-treated mouse skin. In a two-stage skin tumorigenesis study, D-limonene significantly reduced the tumor burden (p < 0.005) and tumor incidence as compared to DMBA/TPA-treated mice. D-Limonene treatment also extended the latency period of tumor development from 4 to 9 weeks. D-Limonene treatment decreased the expression level of Ras, Raf and phosphorylation of extracellular signal-regulated protein kinase 1/2 in DMBA/TPA-induced tumors. A decrease in the expression of Bcl-2 and an increase in Bax expression were also observed in tumor tissues of mice treated with D-limonene. Taken together, our findings suggest that D-limonene may exert its chemopreventive activity through the inhibition of inflammation, oxidative stress and Ras-signaling as well as the induction of pro-apoptotic state during TPA-mediated promotion of DMBA-induced skin cancer in mouse model.

• Authors: S C Chaudhary, M S Siddiqui, M Athar, M Sarwar Alam
• Journal: Human & experimental toxicology (Hum Exp Toxicol) Vol. 31 Issue 8 Pg. 798-811 (Aug 2012) ISSN: 1477-0903 [Electronic] England
• PMID: 22318307 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Carcinogens
• Cyclohexenes
• Terpenes
• 9,10-Dimethyl-1,2-benzanthracene
• Limonene
• Catalase
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• raf Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• ras Proteins
• Glutathione
• Tetradecanoylphorbol Acetate

Topics

• 9,10-Dimethyl-1,2-benzanthracene
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinogens
• Catalase (metabolism)
• Cyclohexenes (pharmacology, therapeutic use)
• Cyclooxygenase 2 (metabolism)
• Female
• Glutathione (metabolism)
• Inflammation (drug therapy, pathology)
• Limonene
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Oxidative Stress (drug effects)
• Signal Transduction (drug effects)
• Skin Neoplasms (chemically induced, metabolism, pathology, prevention & control)
• Terpenes (pharmacology, therapeutic use)
• Tetradecanoylphorbol Acetate
• raf Kinases (metabolism)
• ras Proteins (metabolism)