The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells
Objective To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells. Design Comparative and controlled experimental research study. Setting University research labora...
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| Veröffentlicht in: | Fertility and sterility 2010-03, Vol.93 (4), p.1290-1298 |
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| creator | Grudzien, Meagan M., M.S Low, Philip Steven, Ph.D Manning, Peter C., M.D Arredondo, Melissa, B.S Belton, Robert J., Ph.D Nowak, Romana A., Ph.D |
| description | Objective To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells. Design Comparative and controlled experimental research study. Setting University research laboratory. Patient(s) Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy. Main Outcome Measure(s) The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFβ1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7. Result(s) Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48–72 hours. Halofuginone also significantly reduced collagen type I (α1) and collagen type III (α1) mRNA levels, as well as the profibrotic factor TGFβ1 mRNA levels in both cell types. Conclusion(s) These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas. |
| doi_str_mv | 10.1016/j.fertnstert.2008.11.018 |
| format | Article |
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Design Comparative and controlled experimental research study. Setting University research laboratory. Patient(s) Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy. Main Outcome Measure(s) The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFβ1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7. Result(s) Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48–72 hours. Halofuginone also significantly reduced collagen type I (α1) and collagen type III (α1) mRNA levels, as well as the profibrotic factor TGFβ1 mRNA levels in both cell types. Conclusion(s) These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas.</description><identifier>ISSN: 0015-0282</identifier><identifier>EISSN: 1556-5653</identifier><identifier>DOI: 10.1016/j.fertnstert.2008.11.018</identifier><identifier>PMID: 19135664</identifier><identifier>CODEN: FESTAS</identifier><language>eng</language><publisher>New York, NY: Elsevier Inc</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; antifibrotic ; Antiparasitic agents ; Apoptosis - drug effects ; Apoptosis - physiology ; Biological and medical sciences ; Cell Proliferation - drug effects ; collagen ; Collagen Type I - antagonists & inhibitors ; Collagen Type I - biosynthesis ; Collagen Type III - antagonists & inhibitors ; Collagen Type III - biosynthesis ; Female ; Fibrosis ; Growth Inhibitors - therapeutic use ; Gynecology. Andrology. Obstetrics ; halofuginone ; Humans ; Internal Medicine ; leiomyoma ; Leiomyoma - drug therapy ; Leiomyoma - pathology ; Medical sciences ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - pathology ; myometrium ; Myometrium - drug effects ; Myometrium - pathology ; Obstetrics and Gynecology ; Pharmacology. Drug treatments ; Piperidines - pharmacology ; Piperidines - therapeutic use ; Quinazolinones - pharmacology ; Quinazolinones - therapeutic use ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - biosynthesis ; Tumor Cells, Cultured ; Uterine Neoplasms - drug therapy ; Uterine Neoplasms - pathology</subject><ispartof>Fertility and sterility, 2010-03, Vol.93 (4), p.1290-1298</ispartof><rights>American Society for Reproductive Medicine</rights><rights>2010 American Society for Reproductive Medicine</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.</rights><rights>2009 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-c2aecae8a36a5414a8949189f1730c5ce8611f681ef7a24c4076a9ab0b1a26e53</citedby><cites>FETCH-LOGICAL-c563t-c2aecae8a36a5414a8949189f1730c5ce8611f681ef7a24c4076a9ab0b1a26e53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0015028208045901$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22541250$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19135664$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grudzien, Meagan M., M.S</creatorcontrib><creatorcontrib>Low, Philip Steven, Ph.D</creatorcontrib><creatorcontrib>Manning, Peter C., M.D</creatorcontrib><creatorcontrib>Arredondo, Melissa, B.S</creatorcontrib><creatorcontrib>Belton, Robert J., Ph.D</creatorcontrib><creatorcontrib>Nowak, Romana A., Ph.D</creatorcontrib><title>The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells</title><title>Fertility and sterility</title><addtitle>Fertil Steril</addtitle><description>Objective To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells. Design Comparative and controlled experimental research study. Setting University research laboratory. Patient(s) Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy. Main Outcome Measure(s) The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFβ1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7. Result(s) Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48–72 hours. Halofuginone also significantly reduced collagen type I (α1) and collagen type III (α1) mRNA levels, as well as the profibrotic factor TGFβ1 mRNA levels in both cell types. Conclusion(s) These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>antifibrotic</subject><subject>Antiparasitic agents</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>Cell Proliferation - drug effects</subject><subject>collagen</subject><subject>Collagen Type I - antagonists & inhibitors</subject><subject>Collagen Type I - biosynthesis</subject><subject>Collagen Type III - antagonists & inhibitors</subject><subject>Collagen Type III - biosynthesis</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Growth Inhibitors - therapeutic use</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>halofuginone</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>leiomyoma</subject><subject>Leiomyoma - drug therapy</subject><subject>Leiomyoma - pathology</subject><subject>Medical sciences</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>myometrium</subject><subject>Myometrium - drug effects</subject><subject>Myometrium - pathology</subject><subject>Obstetrics and Gynecology</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - pharmacology</subject><subject>Piperidines - therapeutic use</subject><subject>Quinazolinones - pharmacology</subject><subject>Quinazolinones - therapeutic use</subject><subject>Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Transforming Growth Factor beta - biosynthesis</subject><subject>Tumor Cells, Cultured</subject><subject>Uterine Neoplasms - drug therapy</subject><subject>Uterine Neoplasms - pathology</subject><issn>0015-0282</issn><issn>1556-5653</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNksFu1DAQhiMEotvCKyBfEKddbCd2kkslqIAiVeJAOVsTZ7Lx4tiL7VTaJ-hr43RXLXDiYlueb_4Zz--iIIxuGGXy_W4zYEguprxuOKXNhrENZc2zYsWEkGshRfm8WFHKxJryhp8V5zHuKKWS1fxlccZaVgopq1VxfzsiAZfMYLrgk9GkD_OWjGD9MG-N8w6JcaPpTIpkH7w1uTIk413O6on21sIW3RLqZ_1w3x3IOE_giEXjp4Of4AFdTpiCAUvi5H0ayTRHbZFotDa-Kl4MYCO-Pu0XxY_Pn26vrtc33758vfpws9ZClmmtOaAGbKCUICpWQdNWLWvagdUl1UJjIxkbZMNwqIFXuqK1hBY62jHgEkV5UVwedfdzN2Gv0aUAVu2DmSAclAej_o44M6qtv1O8kbQu2yzw7iQQ_K8ZY1KTicsTwKGfo6rLUtatLGkmmyOpg48x4PBYhVG12Kh26slGtdioGFPZxpz65s8unxJPvmXg7QmAqMEOAZw28ZHjPA-Hi6WHj0cO80zvDAYVtUGnsTcBdVK9N__TzeU_ItoaZ3Ldn3jAuPNzcNkzxVTkiqrvy7dbfh1taCVaysrfO9PbKQ</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Grudzien, Meagan M., M.S</creator><creator>Low, Philip Steven, Ph.D</creator><creator>Manning, Peter C., M.D</creator><creator>Arredondo, Melissa, B.S</creator><creator>Belton, Robert J., Ph.D</creator><creator>Nowak, Romana A., Ph.D</creator><general>Elsevier Inc</general><general>Elsevier</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100301</creationdate><title>The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells</title><author>Grudzien, Meagan M., M.S ; Low, Philip Steven, Ph.D ; Manning, Peter C., M.D ; Arredondo, Melissa, B.S ; Belton, Robert J., Ph.D ; Nowak, Romana A., Ph.D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c563t-c2aecae8a36a5414a8949189f1730c5ce8611f681ef7a24c4076a9ab0b1a26e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>antifibrotic</topic><topic>Antiparasitic agents</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Biological and medical sciences</topic><topic>Cell Proliferation - drug effects</topic><topic>collagen</topic><topic>Collagen Type I - antagonists & inhibitors</topic><topic>Collagen Type I - biosynthesis</topic><topic>Collagen Type III - antagonists & inhibitors</topic><topic>Collagen Type III - biosynthesis</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Growth Inhibitors - therapeutic use</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>halofuginone</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>leiomyoma</topic><topic>Leiomyoma - drug therapy</topic><topic>Leiomyoma - pathology</topic><topic>Medical sciences</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>myometrium</topic><topic>Myometrium - drug effects</topic><topic>Myometrium - pathology</topic><topic>Obstetrics and Gynecology</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - pharmacology</topic><topic>Piperidines - therapeutic use</topic><topic>Quinazolinones - pharmacology</topic><topic>Quinazolinones - therapeutic use</topic><topic>Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Transforming Growth Factor beta - biosynthesis</topic><topic>Tumor Cells, Cultured</topic><topic>Uterine Neoplasms - drug therapy</topic><topic>Uterine Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grudzien, Meagan M., M.S</creatorcontrib><creatorcontrib>Low, Philip Steven, Ph.D</creatorcontrib><creatorcontrib>Manning, Peter C., M.D</creatorcontrib><creatorcontrib>Arredondo, Melissa, B.S</creatorcontrib><creatorcontrib>Belton, Robert J., Ph.D</creatorcontrib><creatorcontrib>Nowak, Romana A., Ph.D</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Fertility and sterility</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grudzien, Meagan M., M.S</au><au>Low, Philip Steven, Ph.D</au><au>Manning, Peter C., M.D</au><au>Arredondo, Melissa, B.S</au><au>Belton, Robert J., Ph.D</au><au>Nowak, Romana A., Ph.D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells</atitle><jtitle>Fertility and sterility</jtitle><addtitle>Fertil Steril</addtitle><date>2010-03-01</date><risdate>2010</risdate><volume>93</volume><issue>4</issue><spage>1290</spage><epage>1298</epage><pages>1290-1298</pages><issn>0015-0282</issn><eissn>1556-5653</eissn><coden>FESTAS</coden><abstract>Objective To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells. Design Comparative and controlled experimental research study. Setting University research laboratory. Patient(s) Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy. Main Outcome Measure(s) The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFβ1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7. Result(s) Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48–72 hours. Halofuginone also significantly reduced collagen type I (α1) and collagen type III (α1) mRNA levels, as well as the profibrotic factor TGFβ1 mRNA levels in both cell types. Conclusion(s) These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas.</abstract><cop>New York, NY</cop><pub>Elsevier Inc</pub><pmid>19135664</pmid><doi>10.1016/j.fertnstert.2008.11.018</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents antifibrotic Antiparasitic agents Apoptosis - drug effects Apoptosis - physiology Biological and medical sciences Cell Proliferation - drug effects collagen Collagen Type I - antagonists & inhibitors Collagen Type I - biosynthesis Collagen Type III - antagonists & inhibitors Collagen Type III - biosynthesis Female Fibrosis Growth Inhibitors - therapeutic use Gynecology. Andrology. Obstetrics halofuginone Humans Internal Medicine leiomyoma Leiomyoma - drug therapy Leiomyoma - pathology Medical sciences Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - pathology myometrium Myometrium - drug effects Myometrium - pathology Obstetrics and Gynecology Pharmacology. Drug treatments Piperidines - pharmacology Piperidines - therapeutic use Quinazolinones - pharmacology Quinazolinones - therapeutic use Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - biosynthesis Tumor Cells, Cultured Uterine Neoplasms - drug therapy Uterine Neoplasms - pathology |
| title | The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells |
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