RRC ID 51608
Author Zenitani M, Nojiri T, Uehara S, Miura K, Hosoda H, Kimura T, Nakahata K, Miyazato M, Okuyama H, Kangawa K.
Title C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells.
Journal Cancer Med
Abstract 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.
Volume 5(5)
Pages 795-805
Published 2016-5
DOI 10.1002/cam4.642
PMID 26816265
PMC PMC4864809
MeSH Adolescent Animals Antineoplastic Combined Chemotherapy Protocols / pharmacology* Cell Proliferation / drug effects Child Child, Preschool Dose-Response Relationship, Drug Drug Synergism Female Humans Infant MAP Kinase Signaling System / drug effects Male Mice, Inbred BALB C Natriuretic Peptide, C-Type / administration & dosage Phosphorylation / drug effects Receptors, Atrial Natriuretic Factor / metabolism Rhabdomyosarcoma / enzymology Rhabdomyosarcoma / pathology* Sildenafil Citrate / administration & dosage Tumor Cells, Cultured Up-Regulation Xenograft Model Antitumor Assays / methods
IF 3.357
Human and Animal Cells RMS-YM (RCB1695)