Pasquali Daniela, Rossi Valentina, Conzo Giovanni, Pannone Giuseppe, Bufo Pantaleo, De Bellis Annamaria, Renzullo Andrea, Bellastella Giuseppe, Colao Annamaria, Vallone Gianfranco, Bellastella Antonio, Sinisi Antonio A
Endocrine Unit, Department of Clinical and Experimental Medicine and Surgery and Endo-Surgery Unit, Second University of Naples, 80131 Naples.
J Mol Endocrinol. 2008 Jun;40(6):263-71. doi: 10.1677/JME-08-0012.
Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor(1-5) mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10(-6) M and SOM230 10(-7) M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.
手术是嗜铬细胞瘤（PHEO）的主要治疗方法，嗜铬细胞瘤是一种分泌儿茶酚胺的肿瘤。良性和恶性PHEO均可复发，而复发性PHEO的术中风险是一个重要的未解决问题。因此，PHEO复发的非手术治疗可以使患者更好地为再次干预做准备，并为他们提供姑息治疗。我们研究了新型生长抑素类似物（帕瑞肽）SOM230与奥曲肽（OCT）在原发性PHEO细胞培养物（Pheo-c）中的作用。建立了来自六个良性手术样本的Pheo-c，并通过免疫细胞化学进行了表征。使用PHEO组织和Pheo-c进行的实时PCR显示生长抑素受体（1-5）mRNA表达水平不同。分析用不同剂量的OCT或SOM230处理48小时和72小时的细胞，以评估它们对细胞增殖、凋亡和儿茶酚胺水平的影响。即使在用OCT或SOM230处理48小时的Pheo-c中观察到细胞活力降低，并且这种作用在72小时后增强，但与OCT相比，在用SOM230处理的Pheo-c中观察到更显著的细胞生长抑制以及更高的凋亡诱导率。特别是，在48小时后检测到Pheo-c中的凋亡，并且与caspase-3和裂解的聚（ADP-核糖）聚合酶的表达和激活增加有关。10^(-6) M的OCT和10^(-7) M的SOM230显著降低了儿茶酚胺水平。我们的结果表明，虽然OCT和SOM230都通过特定受体调节Pheo-c中的细胞生长、凋亡和儿茶酚胺水平，但SOM230更有效。这提高了我们对SOM230在PHEO中的作用机制的认识，并支持其在良性PHEO复发中的可能治疗用途。
