教員業績データベース |
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論文種別 | 原著 |
言語種別 | 英語 |
査読の有無 | 査読あり |
表題 | C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells |
掲載誌名 | 正式名:Cancer medicine 略 称:Cancer Med ISSNコード:2045-7634(Electronic)2045-7634(Linking) |
掲載区分 | 国外 |
巻・号・頁 | 5(5),pp.795-805 |
著者・共著者 | Zenitani Masahiro, Nojiri Takashi, Uehara Shuichiro, Miura Koichi, Hosoda Hiroshi, Kimura Toru, Nakahata Kengo, Miyazato Mikiya, Okuyama Hiroomi, Kangawa Kenji |
発行年月 | 2016/05 |
概要 | Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma in children. Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C-type natriuretic peptide (CNP), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP attenuates proliferation of RMS cells. We examined RMS patient samples and RMS cell lines. All RMS clinical samples expressed higher levels of guanylyl cyclase B (GC-B), the specific receptor for CNP, than RMS cell lines. GC-B expression in RMS cells decreased with the number of passages in vitro. Therefore, GC-B stable expression lines were established to mimic clinical samples. CNP increased cyclic guanosine monophosphate (cGMP) levels in RMS cells in a dose-dependent manner, demonstrating the biological activity of CNP. However, because cGMP is quickly degraded by phosphodiesterases (PDEs), the selective PDE5 inhibitor sildenafil was added to inhibit its degradation. In vitro, CNP, and sildenafil synergistically inhibited proliferation of RMS cells stably expressing GC-B and decreased Raf-1, Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) phosphorylation. These results suggested that CNP in combination with sildenafil exerts antiproliferative effects on RMS cells by inhibiting the Raf/MEK/ERK pathway. This regimen exerted synergistic effects on tumor growth inhibition without severe adverse effects in vivo such as body weight loss. Thus, CNP in combination with sildenafil represents a promising new therapeutic approach against RMS. |
DOI | 10.1002/cam4.642 |
PMID | 26816265 |