D-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis.
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.
Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India.
S C
SC
Chaudhary
M S
MS
Siddiqui
M
M
Athar
M Sarwar
MS
Alam
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002273:Carcinogens; D002374:Catalase / Q000378:metabolism; D053138:Cyclohexenes / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D000077222:Limonene; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013729:Terpenes / Q000494:pharmacology / Q000627:therapeutic use*; D013755:Tetradecanoylphorbol Acetate; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D002273:Carcinogens; D053138:Cyclohexenes; D013729:Terpenes; D015127:9,10-Dimethyl-1,2-benzanthracene; D000077222:Limonene; D002374:Catalase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate