Department of Clinical Physiopathology, DENOthe Center of Excellence for Research, Transfer and High Education, University of Florence, Viale Pieraccini 6, Florence 50139, Italy.
Endocr Relat Cancer. 2010 Feb 18;17(1):169-77. doi: 10.1677/ERC-09-0170. Print 2010 Mar.
Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. The lack of a specific and effective medical treatment is due to the poor knowledge of the mechanisms underlying tumor growth. Research on potential drugs able to specifically interfere with tumor proliferation is essential to develop more efficacious therapies. We evaluated for the first time the in vivo effect of rosiglitazone (RGZ), an anti-diabetic drug with in vitro anti-tumor properties, on ACC proliferation in a xenograft model obtained by s.c. injection of human ACC H295R cells in athymic mice. When the tumor size reached 5 mm, animals were allocated to 5 mg/kg RGZ- or water-treated groups. Tumor volume was measured twice a week. A significant reduction of tumor growth in RGZ versus control (control) group was observed and was already maximal following 17 day treatment (1-T/C=75.4% (43.7-93.8%)). After 31 days of treatment, mice were killed and tumor analyzed. Tumor histological evaluation revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumors presented non infiltrating borders, few vessels, and many apoptotic bodies. Tumor immunohistochemistry showed that Ki-67 was reduced in RGZ versus control group. Quantitative real-time RT-PCR demonstrated a significant reduction in the expression of angiogenic (VEGF), vascular (CD31), proliferation (BMI-1), and anti-apoptotic (Bcl-2) genes in RGZ versus control group tumors. The same inhibitory effects were confirmed in in vitro RGZ-treated H295R. Our findings support and expand the role of RGZ in controlling ACC proliferation and angiogenesis in vivo and in vitro.
肾上腺皮质癌 (ACC) 是一种罕见的侵袭性肿瘤，预后不良。缺乏特异性和有效的治疗方法是由于对肿瘤生长机制的了解不足。研究潜在的能够特异性干扰肿瘤增殖的药物对于开发更有效的治疗方法至关重要。我们首次评估了罗格列酮 (RGZ) 在体内对 ACC 增殖的影响，RGZ 是一种具有体外抗肿瘤特性的抗糖尿病药物，在皮下注射人 ACC H295R 细胞的裸鼠异种移植模型中进行了研究。当肿瘤大小达到 5 毫米时，将动物分配到 5mg/kg RGZ 或水治疗组。每周测量两次肿瘤体积。与对照组相比，RGZ 组的肿瘤生长明显减少，在治疗 17 天后达到最大值（1-T/C=75.4%（43.7-93.8%））。治疗 31 天后，处死小鼠并分析肿瘤。肿瘤组织学评估显示，对照组肿瘤具有侵袭性、富含小血管和有丝分裂象，而 RGZ 组肿瘤边界无浸润、血管较少、凋亡小体较多。肿瘤免疫组化显示，与对照组相比，RGZ 组 Ki-67 减少。实时定量 RT-PCR 表明，与对照组相比，RGZ 组肿瘤中血管生成（VEGF）、血管（CD31）、增殖（BMI-1）和抗凋亡（Bcl-2）基因的表达显著降低。在体外 RGZ 处理的 H295R 中也证实了相同的抑制作用。我们的研究结果支持并扩展了 RGZ 在体内和体外控制 ACC 增殖和血管生成的作用。
