Endocrinology Unit, Department of Medicine, University of Padua, Via Ospedale Civile 105, 35128 Padua, Italy.
Endocr Relat Cancer. 2012 Jul 22;19(4):527-39. doi: 10.1530/ERC-11-0337. Print 2012 Aug.
Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1-2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC.
在肾上腺皮质癌（ACC）患者中，治疗选择有限。基于索拉非尼（一种酪氨酸激酶抑制剂）和依维莫司（一种哺乳动物雷帕霉素靶蛋白抑制剂）在不同组织类型肿瘤中的疗效，我们旨在测试这些药物在肾上腺皮质癌模型中的作用。通过实时 PCR、免疫组化和免疫印迹，研究了 18 例 ACC、33 例醛固酮分泌腺瘤、12 例皮质醇分泌腺瘤和 6 例正常肾上腺皮质中血管内皮生长因子及其受体（VEGFR1-2）的表达。在 SW13 和 H295R 癌细胞系中，通过评估细胞活力和体外细胞凋亡以及肿瘤细胞系异种移植在免疫缺陷小鼠体内的肿瘤生长抑制，测试了索拉非尼和依维莫司单独或联合应用对原代肾上腺皮质培养物和 SW13 和 H295R 细胞的作用。VEGF 和 VEGFR1-2 在所有样本中均有检测到，并且在三分之二的 ACC 标本中表达过度。两种药物单独或联合应用均可观察到 SW13 细胞的细胞活力呈剂量依赖性抑制；药物联合应用可显著增强生长抑制作用。在药物处理的肿瘤细胞中观察到凋亡增加，特别是索拉非尼。最后，在 SW13 异种移植模型中，联合应用这些药物可显著减少肿瘤质量并延长生存时间。我们的数据表明，在 ACC 中可能存在自分泌 VEGF 环。此外，分子靶向药物的联合应用可能具有抗血管生成和直接抗肿瘤作用，因此可能成为治疗 ACC 的新治疗工具。
