Pezzani Raffaele, Rubin Beatrice, Bertazza Loris, Redaelli Marco, Barollo Susi, Monticelli Halenya, Baldini Enke, Mian Caterina, Mucignat Carla, Scaroni Carla, Mantero Franco, Ulisse Salvatore, Iacobone Maurizio, Boscaro Marco
Endocrinology Unit, Department of Medicine, University of Padova, Via Ospedale 105, 35128, Padova, Italy.
Department of Molecular Medicine, University of Padova, Via Marzolo 3, 35131, Padova, Italy.
Invest New Drugs. 2016 Oct;34(5):531-40. doi: 10.1007/s10637-016-0358-3. Epub 2016 May 14.
New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.
对抗癌症需要新的治疗靶点。极光激酶（AK）最近被确定为细胞有丝分裂的重要关键调节因子，因此在临床前和临床研究中作为治疗靶点进行了研究。极光激酶抑制剂（AKI）已在多种癌症类型中进行了研究，但其限制或延缓转移的潜在能力很少被考虑，在肾上腺组织中从未被考虑过。鉴于肾上腺转移瘤和肾上腺皮质癌缺乏有效的药物治疗方法，我们在2种细胞系（H295R和SW13细胞）、3种原发性肾上腺皮质转移瘤细胞培养物（来自肺癌）和4种原发性肾上腺皮质肿瘤细胞培养物中评估了AKI（VX-680、SNS314、ZM447439）。我们还测试了瑞弗桑，它是一种P-糖蛋白抑制剂（一种可排出药物的基本外排泵），并测量了66份肾上腺皮质肿瘤组织样本中的AK表达水平。进行了生物分子和细胞测试（如MTT、胸腺嘧啶核苷测定、瑞氏染色、细胞周期和凋亡分析、蛋白质免疫印迹、定量逆转录聚合酶链反应和突变分析）。我们的结果首次证明了AK在肾上腺皮质癌以及H295R和SW13细胞系中的过表达，从而证明了AKI对肾上腺转移瘤和SW13癌细胞模型的疗效。我们还证明了瑞弗桑和AKI Vx-680在H295R细胞模型中无效，因此不应被视为肾上腺皮质癌的潜在治疗方法。丝氨酸/苏氨酸AK抑制，主要是使用VX-680，可能是一种有前景的、特异性的治疗工具，用于根除肾上腺皮质组织中的转移瘤。
