SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and...
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| Veröffentlicht in: | Oncotarget 2015-02, Vol.6 (6), p.4171-4179 |
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| creator | Park, Jin-hong Ryu, Seung-Hee Choi, Eun Kyung Ahn, Seung Do Park, Euisun Choi, Kyung-Chul Lee, Sang-wook |
| description | Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials. |
| doi_str_mv | 10.18632/oncotarget.2878 |
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SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.2878</identifier><identifier>PMID: 25686821</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Cell Line, Tumor ; Disease Models, Animal ; Fibrosis - etiology ; Fibrosis - prevention & control ; Humans ; Keratinocytes - drug effects ; Keratinocytes - metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Neoplasms - radiotherapy ; Phosphorylation ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Radiation Injuries, Experimental - enzymology ; Radiation Injuries, Experimental - prevention & control ; Radiation-Protective Agents - pharmacology ; Random Allocation ; Receptors, Transforming Growth Factor beta - antagonists & inhibitors ; Receptors, Transforming Growth Factor beta - metabolism ; Research Paper ; Signal Transduction - drug effects ; Smad2 Protein - metabolism ; Smad3 Protein - metabolism</subject><ispartof>Oncotarget, 2015-02, Vol.6 (6), p.4171-4179</ispartof><rights>Copyright: © 2015 Park et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c326t-1be3a1d4e5ba14809c9d6e653e59d32e0acf9289b8b701b926d525b99c46cc813</citedby><cites>FETCH-LOGICAL-c326t-1be3a1d4e5ba14809c9d6e653e59d32e0acf9289b8b701b926d525b99c46cc813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414180/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414180/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25686821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Jin-hong</creatorcontrib><creatorcontrib>Ryu, Seung-Hee</creatorcontrib><creatorcontrib>Choi, Eun Kyung</creatorcontrib><creatorcontrib>Ahn, Seung Do</creatorcontrib><creatorcontrib>Park, Euisun</creatorcontrib><creatorcontrib>Choi, Kyung-Chul</creatorcontrib><creatorcontrib>Lee, Sang-wook</creatorcontrib><title>SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Fibrosis - etiology</subject><subject>Fibrosis - prevention & control</subject><subject>Humans</subject><subject>Keratinocytes - drug effects</subject><subject>Keratinocytes - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neoplasms - radiotherapy</subject><subject>Phosphorylation</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Radiation Injuries, Experimental - enzymology</subject><subject>Radiation Injuries, Experimental - prevention & control</subject><subject>Radiation-Protective Agents - pharmacology</subject><subject>Random Allocation</subject><subject>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Receptors, Transforming Growth Factor beta - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction - drug effects</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - metabolism</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUc1KAzEQDqKoVO-eJEeFrm6ySTa5CCL-FAse1HNIsrNtpN3UJBV8LR_EZ3K1WnUuM_D9zAwfQgekPCFSVPQ0dC5kEyeQT6is5QbaJYqpgnJebf6Zd9B-Sk9lX5zVkqpttEO5kEJSsosm97cjSgQdYtNh30299TlEHFqcp4Afrq-K9zecXxeARziCg8UnenQ-vuXHwx9-wtE03mQfusJ3zdJBg1tvY0g-9Rw89w720FZrZgn2v_sAPV5dPlzcFOO769HF-bhwFRW5IBYqQxoG3BrCZKmcagQIXgFXTUWhNK5VVCorbV0Sq6hoOOVWKceEc5JUA3S28l0s7RwaB12OZqYX0c9NfNXBeP0f6fxUT8KLZowwIsve4OjbIIbnJaSs5z45mM1MB2GZNBGC1bWQhPbUckV1_aspQrteQ0r9FZH-jUh_RtRLDv-etxb8BFJ9ANPej4I</recordid><startdate>20150228</startdate><enddate>20150228</enddate><creator>Park, Jin-hong</creator><creator>Ryu, Seung-Hee</creator><creator>Choi, Eun Kyung</creator><creator>Ahn, Seung Do</creator><creator>Park, Euisun</creator><creator>Choi, Kyung-Chul</creator><creator>Lee, Sang-wook</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150228</creationdate><title>SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice</title><author>Park, Jin-hong ; Ryu, Seung-Hee ; Choi, Eun Kyung ; Ahn, Seung Do ; Park, Euisun ; Choi, Kyung-Chul ; Lee, Sang-wook</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c326t-1be3a1d4e5ba14809c9d6e653e59d32e0acf9289b8b701b926d525b99c46cc813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Fibrosis - etiology</topic><topic>Fibrosis - prevention & control</topic><topic>Humans</topic><topic>Keratinocytes - drug effects</topic><topic>Keratinocytes - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neoplasms - radiotherapy</topic><topic>Phosphorylation</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Radiation Injuries, Experimental - enzymology</topic><topic>Radiation Injuries, Experimental - prevention & control</topic><topic>Radiation-Protective Agents - pharmacology</topic><topic>Random Allocation</topic><topic>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Receptors, Transforming Growth Factor beta - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction - drug effects</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Park, Jin-hong</creatorcontrib><creatorcontrib>Ryu, Seung-Hee</creatorcontrib><creatorcontrib>Choi, Eun Kyung</creatorcontrib><creatorcontrib>Ahn, Seung Do</creatorcontrib><creatorcontrib>Park, Euisun</creatorcontrib><creatorcontrib>Choi, Kyung-Chul</creatorcontrib><creatorcontrib>Lee, Sang-wook</creatorcontrib><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>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Jin-hong</au><au>Ryu, Seung-Hee</au><au>Choi, Eun Kyung</au><au>Ahn, Seung Do</au><au>Park, Euisun</au><au>Choi, Kyung-Chul</au><au>Lee, Sang-wook</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-02-28</date><risdate>2015</risdate><volume>6</volume><issue>6</issue><spage>4171</spage><epage>4179</epage><pages>4171-4179</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>25686821</pmid><doi>10.18632/oncotarget.2878</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; PubMed Central; Free E- Journals |
| subjects | Animals Cell Line, Tumor Disease Models, Animal Fibrosis - etiology Fibrosis - prevention & control Humans Keratinocytes - drug effects Keratinocytes - metabolism Male Mice Mice, Inbred BALB C Neoplasms - radiotherapy Phosphorylation Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Radiation Injuries, Experimental - enzymology Radiation Injuries, Experimental - prevention & control Radiation-Protective Agents - pharmacology Random Allocation Receptors, Transforming Growth Factor beta - antagonists & inhibitors Receptors, Transforming Growth Factor beta - metabolism Research Paper Signal Transduction - drug effects Smad2 Protein - metabolism Smad3 Protein - metabolism |
| title | SKI2162, an inhibitor of the TGF-β type I receptor (ALK5), inhibits radiation-induced fibrosis in mice |
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