Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a highly vascular tumor, and treatment options for patients of advanced-stage are limited. Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin...
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| Veröffentlicht in: | Oncology reports 2016-08, Vol.36 (2), p.669-675 |
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| creator | Dai, Youguo Cui, Jin Gan, Ping Li, Weiming |
| description | Hepatocellular carcinoma (HCC) is a highly vascular tumor, and treatment options for patients of advanced-stage are limited. Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an essential cofactor eNOS and represents a critical determinant of NO production. To examine whether treatment of 2,4-diamino-6-hydroxypyrimidine (DAHP) inhibits angiogenesis of HCC, BALB/c-nu mice were injected with HepG-2 cells with DAHP. Supplemental DAHP treatment decreased K-ras mRNA transcripts, inhibition of phosphorylation of eNOS and Akt, inhibition of guanosine triphosphate cyclohydrolase (GTPCH), and decreased significantly NO synthesis, and then inhibited angiogenesis, compared with the results observed in the saline group. Histopathology demonstrated angiogenesis and tumor formation were significantly inhibited in HCC. DAHP downregulates GTPCH protein expression, corresponding to decreased levels of BH4 and the contents of NO. In addition, DAHP downregulates eNOS and Akt protein expression, corresponding to decreased eNOS phosphorylation at Ser1177 and Akt phosphorylation, compared with the saline control. We suggest that DAHP, recognized as a specific competitive inhibitor of GTPCH, can decrease tumor BH4 and NO by the inhibition of the wild-type Ras-PI3K/Akt pathway, and then inhibiting angiogenesis, and may provide a novel and promising way to target BH4 synthetic pathways to inhibit angiogenesis and to control potential progression of HCC. Whether DAHP has a therapeutic potential will require more direct testing in humans. |
| doi_str_mv | 10.3892/or.2016.4850 |
| format | Article |
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Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an essential cofactor eNOS and represents a critical determinant of NO production. To examine whether treatment of 2,4-diamino-6-hydroxypyrimidine (DAHP) inhibits angiogenesis of HCC, BALB/c-nu mice were injected with HepG-2 cells with DAHP. Supplemental DAHP treatment decreased K-ras mRNA transcripts, inhibition of phosphorylation of eNOS and Akt, inhibition of guanosine triphosphate cyclohydrolase (GTPCH), and decreased significantly NO synthesis, and then inhibited angiogenesis, compared with the results observed in the saline group. Histopathology demonstrated angiogenesis and tumor formation were significantly inhibited in HCC. DAHP downregulates GTPCH protein expression, corresponding to decreased levels of BH4 and the contents of NO. In addition, DAHP downregulates eNOS and Akt protein expression, corresponding to decreased eNOS phosphorylation at Ser1177 and Akt phosphorylation, compared with the saline control. We suggest that DAHP, recognized as a specific competitive inhibitor of GTPCH, can decrease tumor BH4 and NO by the inhibition of the wild-type Ras-PI3K/Akt pathway, and then inhibiting angiogenesis, and may provide a novel and promising way to target BH4 synthetic pathways to inhibit angiogenesis and to control potential progression of HCC. Whether DAHP has a therapeutic potential will require more direct testing in humans.</description><identifier>ISSN: 1021-335X</identifier><identifier>EISSN: 1791-2431</identifier><identifier>DOI: 10.3892/or.2016.4850</identifier><identifier>PMID: 27279530</identifier><language>eng</language><publisher>Greece: D.A. Spandidos</publisher><subject>2,4-diamino-6-hydroxypyrimidine ; Angiogenesis ; Animals ; Apoptosis ; Biopterins - analogs & derivatives ; Biopterins - genetics ; Biosynthesis ; Carcinoma, Hepatocellular - genetics ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Coenzymes ; Development and progression ; Down-Regulation - drug effects ; Down-Regulation - genetics ; endothelial nitric oxide synthase ; Genes, ras - genetics ; Genetic aspects ; Health aspects ; Hep G2 Cells ; hepatocellular carcinoma ; Hepatoma ; Humans ; Hypoxanthines - pharmacology ; Kinases ; Laboratory animals ; Liver cancer ; Liver Neoplasms - genetics ; Metastasis ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neovascularization ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - pathology ; Nitric oxide ; Nitric Oxide - genetics ; Nitric Oxide Synthase Type III - genetics ; Phosphatidylinositol 3-Kinases - genetics ; Phosphorylation ; Phosphorylation - drug effects ; Phosphorylation - genetics ; Physiology ; Protein expression ; Proteins ; Proto-Oncogene Proteins c-akt - genetics ; RNA, Messenger - genetics ; Rodents ; Studies ; tetrahydrobiopterin ; Tumors ; Vein & artery diseases</subject><ispartof>Oncology reports, 2016-08, Vol.36 (2), p.669-675</ispartof><rights>Copyright: © Dai et al.</rights><rights>COPYRIGHT 2016 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2016</rights><rights>Copyright: © Dai et al. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-71a21f6a712177568d923580255f3f665d4dea7e73036618ce3fbd24f71c5eca3</citedby><cites>FETCH-LOGICAL-c541t-71a21f6a712177568d923580255f3f665d4dea7e73036618ce3fbd24f71c5eca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27279530$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dai, Youguo</creatorcontrib><creatorcontrib>Cui, Jin</creatorcontrib><creatorcontrib>Gan, Ping</creatorcontrib><creatorcontrib>Li, Weiming</creatorcontrib><title>Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma</title><title>Oncology reports</title><addtitle>Oncol Rep</addtitle><description>Hepatocellular carcinoma (HCC) is a highly vascular tumor, and treatment options for patients of advanced-stage are limited. Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an essential cofactor eNOS and represents a critical determinant of NO production. To examine whether treatment of 2,4-diamino-6-hydroxypyrimidine (DAHP) inhibits angiogenesis of HCC, BALB/c-nu mice were injected with HepG-2 cells with DAHP. Supplemental DAHP treatment decreased K-ras mRNA transcripts, inhibition of phosphorylation of eNOS and Akt, inhibition of guanosine triphosphate cyclohydrolase (GTPCH), and decreased significantly NO synthesis, and then inhibited angiogenesis, compared with the results observed in the saline group. Histopathology demonstrated angiogenesis and tumor formation were significantly inhibited in HCC. DAHP downregulates GTPCH protein expression, corresponding to decreased levels of BH4 and the contents of NO. In addition, DAHP downregulates eNOS and Akt protein expression, corresponding to decreased eNOS phosphorylation at Ser1177 and Akt phosphorylation, compared with the saline control. We suggest that DAHP, recognized as a specific competitive inhibitor of GTPCH, can decrease tumor BH4 and NO by the inhibition of the wild-type Ras-PI3K/Akt pathway, and then inhibiting angiogenesis, and may provide a novel and promising way to target BH4 synthetic pathways to inhibit angiogenesis and to control potential progression of HCC. Whether DAHP has a therapeutic potential will require more direct testing in humans.</description><subject>2,4-diamino-6-hydroxypyrimidine</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biopterins - analogs & derivatives</subject><subject>Biopterins - genetics</subject><subject>Biosynthesis</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Coenzymes</subject><subject>Development and progression</subject><subject>Down-Regulation - drug effects</subject><subject>Down-Regulation - genetics</subject><subject>endothelial nitric oxide synthase</subject><subject>Genes, ras - genetics</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hep G2 Cells</subject><subject>hepatocellular carcinoma</subject><subject>Hepatoma</subject><subject>Humans</subject><subject>Hypoxanthines - pharmacology</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - genetics</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Neovascularization</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - genetics</subject><subject>Nitric Oxide Synthase Type III - genetics</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Phosphorylation - genetics</subject><subject>Physiology</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>RNA, Messenger - genetics</subject><subject>Rodents</subject><subject>Studies</subject><subject>tetrahydrobiopterin</subject><subject>Tumors</subject><subject>Vein & artery diseases</subject><issn>1021-335X</issn><issn>1791-2431</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkktr3DAUhU1padK0u66LoNBVPdHDkuxNYZI-YaCbFroTGvnaVrAlR5IT8u8rkzSTgaKFhO6nI92jUxRvCd6wuqHnPmwoJmJT1Rw_K06JbEhJK0ae5zWmpGSM_zkpXsV4hTGVWDQvixMqqWw4w6fF9Wd_6wL0y6iT9Q75DiVIQQ93bfB76-cEwTpk3WD3NkWUlskHpF1vfQ8Ooo25hi62u4tzU7oFTdYAurVpQAPMOnkD45i1AzI6GOv8pF8XLzo9RnjzMJ8Vv79--XX5vdz9_PbjcrsrDa9IKiXRlHRCS0KJlFzUbUMZrzHlvGOdELytWtASJMNMCFIbYN2-pVUnieFgNDsrPt3rzst-gtaAy22Nag520uFOeW3VccXZQfX-RlVNtqziWeD9g0Dw1wvEpK78Elx-syINo0I0VVMdqF6PoKzrfBYzk41GbSveCF5TtlKb_1B5tJAd8w46m_ePDnx4cmAAPaYh-nFZPykegx_vQRN8jAG6xw4JVmtAlA9qDYhaA5Lxd09deYT_JeJwcZy1a23r48GyUDJRYlri3Dv7C7irw1A</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Dai, Youguo</creator><creator>Cui, Jin</creator><creator>Gan, Ping</creator><creator>Li, Weiming</creator><general>D.A. Spandidos</general><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</general><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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20160801</creationdate><title>Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma</title><author>Dai, Youguo ; Cui, Jin ; Gan, Ping ; Li, Weiming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-71a21f6a712177568d923580255f3f665d4dea7e73036618ce3fbd24f71c5eca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>2,4-diamino-6-hydroxypyrimidine</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biopterins - analogs & derivatives</topic><topic>Biopterins - genetics</topic><topic>Biosynthesis</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Coenzymes</topic><topic>Development and progression</topic><topic>Down-Regulation - drug effects</topic><topic>Down-Regulation - genetics</topic><topic>endothelial nitric oxide synthase</topic><topic>Genes, ras - genetics</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hep G2 Cells</topic><topic>hepatocellular carcinoma</topic><topic>Hepatoma</topic><topic>Humans</topic><topic>Hypoxanthines - pharmacology</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - genetics</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Neovascularization</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>Neovascularization, Pathologic - pathology</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - genetics</topic><topic>Nitric Oxide Synthase Type III - genetics</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Phosphorylation - genetics</topic><topic>Physiology</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>RNA, Messenger - genetics</topic><topic>Rodents</topic><topic>Studies</topic><topic>tetrahydrobiopterin</topic><topic>Tumors</topic><topic>Vein & artery diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dai, Youguo</creatorcontrib><creatorcontrib>Cui, Jin</creatorcontrib><creatorcontrib>Gan, Ping</creatorcontrib><creatorcontrib>Li, Weiming</creatorcontrib><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>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>British Nursing Database</collection><collection>ProQuest Central</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>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>PubMed Central (Full Participant titles)</collection><jtitle>Oncology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dai, Youguo</au><au>Cui, Jin</au><au>Gan, Ping</au><au>Li, Weiming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma</atitle><jtitle>Oncology reports</jtitle><addtitle>Oncol Rep</addtitle><date>2016-08-01</date><risdate>2016</risdate><volume>36</volume><issue>2</issue><spage>669</spage><epage>675</epage><pages>669-675</pages><issn>1021-335X</issn><eissn>1791-2431</eissn><abstract>Hepatocellular carcinoma (HCC) is a highly vascular tumor, and treatment options for patients of advanced-stage are limited. Nitric oxide (NO), which is derived from endothelial nitric oxide synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an essential cofactor eNOS and represents a critical determinant of NO production. To examine whether treatment of 2,4-diamino-6-hydroxypyrimidine (DAHP) inhibits angiogenesis of HCC, BALB/c-nu mice were injected with HepG-2 cells with DAHP. Supplemental DAHP treatment decreased K-ras mRNA transcripts, inhibition of phosphorylation of eNOS and Akt, inhibition of guanosine triphosphate cyclohydrolase (GTPCH), and decreased significantly NO synthesis, and then inhibited angiogenesis, compared with the results observed in the saline group. Histopathology demonstrated angiogenesis and tumor formation were significantly inhibited in HCC. DAHP downregulates GTPCH protein expression, corresponding to decreased levels of BH4 and the contents of NO. In addition, DAHP downregulates eNOS and Akt protein expression, corresponding to decreased eNOS phosphorylation at Ser1177 and Akt phosphorylation, compared with the saline control. We suggest that DAHP, recognized as a specific competitive inhibitor of GTPCH, can decrease tumor BH4 and NO by the inhibition of the wild-type Ras-PI3K/Akt pathway, and then inhibiting angiogenesis, and may provide a novel and promising way to target BH4 synthetic pathways to inhibit angiogenesis and to control potential progression of HCC. Whether DAHP has a therapeutic potential will require more direct testing in humans.</abstract><cop>Greece</cop><pub>D.A. Spandidos</pub><pmid>27279530</pmid><doi>10.3892/or.2016.4850</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | 2,4-diamino-6-hydroxypyrimidine Angiogenesis Animals Apoptosis Biopterins - analogs & derivatives Biopterins - genetics Biosynthesis Carcinoma, Hepatocellular - genetics Cell cycle Cell growth Cell Line, Tumor Coenzymes Development and progression Down-Regulation - drug effects Down-Regulation - genetics endothelial nitric oxide synthase Genes, ras - genetics Genetic aspects Health aspects Hep G2 Cells hepatocellular carcinoma Hepatoma Humans Hypoxanthines - pharmacology Kinases Laboratory animals Liver cancer Liver Neoplasms - genetics Metastasis Mice Mice, Inbred BALB C Mice, Nude Neovascularization Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Nitric oxide Nitric Oxide - genetics Nitric Oxide Synthase Type III - genetics Phosphatidylinositol 3-Kinases - genetics Phosphorylation Phosphorylation - drug effects Phosphorylation - genetics Physiology Protein expression Proteins Proto-Oncogene Proteins c-akt - genetics RNA, Messenger - genetics Rodents Studies tetrahydrobiopterin Tumors Vein & artery diseases |
| title | Downregulation of tetrahydrobiopterin inhibits tumor angiogenesis in BALB/c-nu mice with hepatocellular carcinoma |
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