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Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C\u2010type natriuretic peptide (CNP<\/jats:styled-content>), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP<\/jats:styled-content> attenuates proliferation of RMS<\/jats:styled-content> cells. We examined RMS<\/jats:styled-content> patient samples and RMS<\/jats:styled-content> cell lines. All RMS<\/jats:styled-content> clinical samples expressed higher levels of guanylyl cyclase B (GC<\/jats:styled-content>\u2010B), the specific receptor for CNP<\/jats:styled-content>, than RMS<\/jats:styled-content> cell lines. GC<\/jats:styled-content>\u2010B expression in RMS<\/jats:styled-content> cells decreased with the number of passages in vitro. Therefore, GC<\/jats:styled-content>\u2010B stable expression lines were established to mimic clinical samples. CNP<\/jats:styled-content> increased cyclic guanosine monophosphate (cGMP<\/jats:styled-content>) levels in RMS<\/jats:styled-content> cells in a dose\u2010dependent manner, demonstrating the biological activity of CNP<\/jats:styled-content>. However, because cGMP<\/jats:styled-content> is quickly degraded by phosphodiesterases (PDE<\/jats:styled-content>s), the selective PDE<\/jats:styled-content>5 inhibitor sildenafil was added to inhibit its degradation. In vitro, CNP<\/jats:styled-content>, and sildenafil synergistically inhibited proliferation of RMS<\/jats:styled-content> cells stably expressing GC<\/jats:styled-content>\u2010B and decreased Raf\u20101, Mitogen\u2010activated protein kinase kinase (MEK<\/jats:styled-content>), and extracellular signal\u2010regulated kinase (ERK<\/jats:styled-content>) phosphorylation. These results suggested that CNP<\/jats:styled-content> in combination with sildenafil exerts antiproliferative effects on RMS<\/jats:styled-content> cells by inhibiting the Raf\/MEK<\/jats:styled-content>\/ERK<\/jats:styled-content> pathway. This regimen exerted synergistic effects on tumor growth inhibition without severe adverse effects in vivo such as body weight loss. Thus, CNP<\/jats:styled-content> in combination with sildenafil represents a promising new therapeutic approach against RMS.<\/jats:p>","DOI":"10.1002\/cam4.642","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T03:16:58Z","timestamp":1453864618000},"page":"795-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["C\u2010type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells"],"prefix":"10.1002","volume":"5","author":[{"given":"Masahiro","family":"Zenitani","sequence":"first","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"},{"name":"Department of Pediatric Surgery Osaka University Graduate School of Medicine Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Nojiri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichiro","family":"Uehara","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Osaka University Graduate School of Medicine Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Miura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Hosoda","sequence":"additional","affiliation":[{"name":"Departments of Regenerative Medicine and Tissue Engineering National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kengo","family":"Nakahata","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Osaka University Graduate School of Medicine Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikiya","family":"Miyazato","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroomi","family":"Okuyama","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery Osaka University Graduate School of Medicine Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kangawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry National Cerebral and Cardiovascular Center Research Institute Suita\u2010City Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,1,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199102143240706"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24465"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(90)92401-K"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(91)90627-J"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(97)00086-2"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1998.00895.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000045836"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00005140"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.10.067"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.7.4293"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510019103"},{"key":"e_1_2_7_13_1","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/j.1742-1241.1998.tb08886.x","article-title":"Efficacy and safety of oral sildenafil in the treatment of erectile dysfunction: a double\u2010blind, placebo\u2010controlled study of 329 patients. 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