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 (...
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| description | 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) [3H] 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. |
| doi_str_mv | 10.1177/0960327111434948 |
| format | Article |
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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) [3H] 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.</description><identifier>ISSN: 0960-3271</identifier><identifier>EISSN: 1477-0903</identifier><identifier>DOI: 10.1177/0960327111434948</identifier><identifier>PMID: 22318307</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>12-O-Tetradecanoylphorbol-13-acetate ; 9,10-Dimethyl-1,2-benzanthracene ; Animal models ; Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Bax protein ; Bcl-2 protein ; Biological and medical sciences ; Body weight ; Carcinogenesis, carcinogens and anticarcinogens ; Carcinogens ; Catalase ; Catalase - metabolism ; Chemical agents ; Cyclohexenes - pharmacology ; Cyclohexenes - therapeutic use ; Cyclooxygenase 2 - metabolism ; Cyclooxygenase-2 ; DNA ; Edema ; Female ; Glutathione - metabolism ; Glutathione peroxidase ; glutathione reductase ; Glutathione transferase ; Hyperplasia ; Inflammation ; Inflammation - drug therapy ; Inflammation - pathology ; Limonene ; Malondialdehyde ; Medical sciences ; Mice ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Ornithine decarboxylase ; Oxidative stress ; Oxidative Stress - drug effects ; Phosphorylation ; Protein kinase ; raf Kinases - metabolism ; Raf protein ; Ras protein ; ras Proteins - metabolism ; Rodents ; Signal Transduction - drug effects ; Skin cancer ; Skin Neoplasms - chemically induced ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Skin Neoplasms - prevention & control ; Terpenes - pharmacology ; Terpenes - therapeutic use ; Tetradecanoylphorbol Acetate ; Thymidine ; Toxicology ; Tumorigenesis ; Tumors</subject><ispartof>Human & experimental toxicology, 2012-08, Vol.31 (8), p.798-811</ispartof><rights>The Author(s) 2012</rights><rights>2014 INIST-CNRS</rights><rights>SAGE Publications © Aug 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c494t-ceff66b51ea41d0b4fe747858b20f2a0c0dca6ea581d33d5631699a8e0a4531c3</citedby><cites>FETCH-LOGICAL-c494t-ceff66b51ea41d0b4fe747858b20f2a0c0dca6ea581d33d5631699a8e0a4531c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/0960327111434948$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/0960327111434948$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,776,780,21945,27830,27901,27902,44921,45309</link.rule.ids><linktorsrc>$$Uhttps://journals.sagepub.com/doi/full/10.1177/0960327111434948?utm_source=summon&utm_medium=discovery-provider$$EView_record_in_SAGE_Publications$$FView_record_in_$$GSAGE_Publications</linktorsrc><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26875477$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22318307$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chaudhary, SC</creatorcontrib><creatorcontrib>Siddiqui, MS</creatorcontrib><creatorcontrib>Athar, M</creatorcontrib><creatorcontrib>Alam, M Sarwar</creatorcontrib><title>d-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis</title><title>Human & experimental toxicology</title><addtitle>Hum Exp Toxicol</addtitle><description>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) [3H] 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.</description><subject>12-O-Tetradecanoylphorbol-13-acetate</subject><subject>9,10-Dimethyl-1,2-benzanthracene</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Bax protein</subject><subject>Bcl-2 protein</subject><subject>Biological and medical sciences</subject><subject>Body weight</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>Carcinogens</subject><subject>Catalase</subject><subject>Catalase - metabolism</subject><subject>Chemical agents</subject><subject>Cyclohexenes - pharmacology</subject><subject>Cyclohexenes - therapeutic use</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cyclooxygenase-2</subject><subject>DNA</subject><subject>Edema</subject><subject>Female</subject><subject>Glutathione - metabolism</subject><subject>Glutathione peroxidase</subject><subject>glutathione reductase</subject><subject>Glutathione transferase</subject><subject>Hyperplasia</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - pathology</subject><subject>Limonene</subject><subject>Malondialdehyde</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Ornithine decarboxylase</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Phosphorylation</subject><subject>Protein kinase</subject><subject>raf Kinases - metabolism</subject><subject>Raf protein</subject><subject>Ras protein</subject><subject>ras Proteins - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction - drug effects</subject><subject>Skin cancer</subject><subject>Skin Neoplasms - chemically induced</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>Skin Neoplasms - prevention & control</subject><subject>Terpenes - pharmacology</subject><subject>Terpenes - therapeutic use</subject><subject>Tetradecanoylphorbol Acetate</subject><subject>Thymidine</subject><subject>Toxicology</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0960-3271</issn><issn>1477-0903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqN0cuLFDEQB-Agijuu3j1JQAQPtlY63XkcZVkfOCAsem6q0-ndrN2dMZVW9783w4wPFgRPCdRXlRQ_xh4LeCmE1q_AKpC1FkI0srGNucM2otG6AgvyLtvsy9W-fsIeEF0DgLKtuM9O6loKI0Fv2DRU2zDHxS-ez3FYJ8yeeFjGCecZc4jLCx5_hKFcv3lOOXkijsvAL5Cq84sPfIf56jve8BxL11XoQ-bzmkIZR1_CwvM6xxQuy3gK9JDdG3Ei_-h4nrLPb84_nb2rth_fvj97va1cWSJXzo-jUn0rPDZigL4ZvW60aU1fw1gjOBgcKo-tEYOUQ6ukUNai8YBNK4WTp-z5Ye4uxa-rp9zNgZyfJlx8XKkTII0SYKX9H9oIa5Q1hT69Ra_jmpayyF5JbeoW6qLgoFyKRMmP3S6FGdNNQd0-tO52aKXlyXHw2s9--N3wK6UCnh0BksNpTLi4QH-cMrotsRdXHRzhpf_7d_94-CcoHqs6</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>Chaudhary, SC</creator><creator>Siddiqui, MS</creator><creator>Athar, M</creator><creator>Alam, M Sarwar</creator><general>SAGE Publications</general><general>Sage Publications</general><general>Sage Publications Ltd</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7ST</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>SOI</scope><scope>7X8</scope><scope>7TO</scope><scope>H94</scope></search><sort><creationdate>20120801</creationdate><title>d-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis</title><author>Chaudhary, SC ; Siddiqui, MS ; Athar, M ; Alam, M Sarwar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c494t-ceff66b51ea41d0b4fe747858b20f2a0c0dca6ea581d33d5631699a8e0a4531c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>12-O-Tetradecanoylphorbol-13-acetate</topic><topic>9,10-Dimethyl-1,2-benzanthracene</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Bax protein</topic><topic>Bcl-2 protein</topic><topic>Biological and medical sciences</topic><topic>Body weight</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Carcinogens</topic><topic>Catalase</topic><topic>Catalase - metabolism</topic><topic>Chemical agents</topic><topic>Cyclohexenes - pharmacology</topic><topic>Cyclohexenes - therapeutic use</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cyclooxygenase-2</topic><topic>DNA</topic><topic>Edema</topic><topic>Female</topic><topic>Glutathione - metabolism</topic><topic>Glutathione peroxidase</topic><topic>glutathione reductase</topic><topic>Glutathione transferase</topic><topic>Hyperplasia</topic><topic>Inflammation</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - pathology</topic><topic>Limonene</topic><topic>Malondialdehyde</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Ornithine decarboxylase</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Phosphorylation</topic><topic>Protein kinase</topic><topic>raf Kinases - metabolism</topic><topic>Raf protein</topic><topic>Ras protein</topic><topic>ras Proteins - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction - drug effects</topic><topic>Skin cancer</topic><topic>Skin Neoplasms - chemically induced</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>Skin Neoplasms - prevention & control</topic><topic>Terpenes - pharmacology</topic><topic>Terpenes - therapeutic use</topic><topic>Tetradecanoylphorbol Acetate</topic><topic>Thymidine</topic><topic>Toxicology</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chaudhary, SC</creatorcontrib><creatorcontrib>Siddiqui, MS</creatorcontrib><creatorcontrib>Athar, M</creatorcontrib><creatorcontrib>Alam, M Sarwar</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Environment Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Human & experimental toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Chaudhary, SC</au><au>Siddiqui, MS</au><au>Athar, M</au><au>Alam, M Sarwar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>d-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis</atitle><jtitle>Human & experimental toxicology</jtitle><addtitle>Hum Exp Toxicol</addtitle><date>2012-08-01</date><risdate>2012</risdate><volume>31</volume><issue>8</issue><spage>798</spage><epage>811</epage><pages>798-811</pages><issn>0960-3271</issn><eissn>1477-0903</eissn><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) [3H] 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.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>22318307</pmid><doi>10.1177/0960327111434948</doi><tpages>14</tpages></addata></record> |
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| subjects | 12-O-Tetradecanoylphorbol-13-acetate 9,10-Dimethyl-1,2-benzanthracene Animal models Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Bax protein Bcl-2 protein Biological and medical sciences Body weight Carcinogenesis, carcinogens and anticarcinogens Carcinogens Catalase Catalase - metabolism Chemical agents Cyclohexenes - pharmacology Cyclohexenes - therapeutic use Cyclooxygenase 2 - metabolism Cyclooxygenase-2 DNA Edema Female Glutathione - metabolism Glutathione peroxidase glutathione reductase Glutathione transferase Hyperplasia Inflammation Inflammation - drug therapy Inflammation - pathology Limonene Malondialdehyde Medical sciences Mice Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Ornithine decarboxylase Oxidative stress Oxidative Stress - drug effects Phosphorylation Protein kinase raf Kinases - metabolism Raf protein Ras protein ras Proteins - metabolism Rodents Signal Transduction - drug effects Skin cancer Skin Neoplasms - chemically induced Skin Neoplasms - metabolism Skin Neoplasms - pathology Skin Neoplasms - prevention & control Terpenes - pharmacology Terpenes - therapeutic use Tetradecanoylphorbol Acetate Thymidine Toxicology Tumorigenesis Tumors |
| title | d-Limonene modulates inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis |
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