C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells.
C-type natriuretic peptide in combination with sildenafil attenuates proliferation of rhabdomyosarcoma cells.
复制标题
C型纳特里尿肽与西地那非结合减弱了横纹肌肉瘤细胞的增殖。
DOI：
10.1002/cam4.642
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发表时间：
2016-05
期刊：
影响因子：
4
通讯作者：
Kangawa K
中科院分区：
文献类型：
--
作者：
Zenitani M;Nojiri T;Uehara S;Miura K;Hosoda H;Kimura T;Nakahata K;Miyazato M;Okuyama H;Kangawa K
横纹肌肉瘤（RMS）是一种恶性间叶肿瘤，也是儿童最常见的软组织肉瘤。由于与强化多模式治疗相关的几种并发症，包括生长障碍和继发性癌症，迫切需要毒性较小的新疗法。C型利钠肽（CNP）是一种由内皮细胞分泌的内源性肽，在多种类型的间充质细胞中发挥抗增殖作用。因此，我们研究CNP是否减弱RMS细胞的增殖。我们检查了RMS患者样品和RMS细胞系。所有RMS临床样本表达的鸟苷酸环化酶B（GC-B）（CNP的特异性受体）水平均高于RMS细胞系。GC B在RMS细胞中的表达随传代次数的增加而降低。因此，建立GC-B稳定表达系以模拟临床样品。CNP以剂量依赖性方式增加RMS细胞中的环磷酸鸟苷（cGMP）水平，证明了CNP的生物活性。然而，由于cGMP被磷酸二酯酶（PDE）快速降解，因此添加选择性PDE 5抑制剂西地那非以抑制其降解。在体外，CNP和西地那非协同抑制稳定表达GC-B的RMS细胞的增殖，并降低Raf-1、促分裂原活化蛋白激酶激酶（MEK）和细胞外信号调节激酶（ERK）磷酸化。这些结果表明，CNP与西地那非联合给药通过抑制Raf/MEK/ERK通路对RMS细胞发挥抗增殖作用。该方案对肿瘤生长抑制产生协同作用，而在体内没有严重的副作用，如体重减轻。因此，CNP与西地那非联合治疗代表了一种有前景的治疗RMS的新方法。
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.