Department of Surgery, Philipps-University of Marburg, Baldingerstrasse, 35043, Marburg, Germany.
Endocrine. 2012 Dec;42(3):637-46. doi: 10.1007/s12020-012-9665-4. Epub 2012 Apr 5.
Conventional treatment by surgery, radioiodine, and thyroxin-suppressive therapy often fails to cure anaplastic thyroid cancer (ATC). Therefore several attempts have been made to evaluate new therapy options by use of "small molecule inhibitors". ATC was shown to respond to monotherapeutic proteasome and Aurora kinase inhibition in vitro as well as in xenotransplanted tumor cells. Aim of this study was to evaluate the effect of combined treatment targeting the ubiquitin-proteasome system by bortezomib and Aurora kinases by use of MLN8054. Three ATC cell lines (Hth74, C643, and Kat4.1) were used. The antiproliferative effect of combined treatment with bortezomib and MLN8054 was assessed by MTT-assay and cell cycle analysis (FACS). Proapoptotic effects were evaluated by measurement of Caspase-3 activity, and effects on VEGF secretion were analyzed by ELISA. Compared to mono-application combined treatment with bortezomib and MLN8054 resulted in a further decrease of cell density, whereas antagonizing effects were found regarding cell cycle progression. Caspase-3 activity was increased up to 2.7- and 14-fold by mono-application of MLN8054 and bortezomib, respectively. When the two drugs were used in combination, a further enhancement of Caspase-3 activity was achieved, depending on the cell line. VEGF secretion was decreased following bortezomib treatment and remained unchanged by MLN8054. Only in C643 cells, the bortezomib-induced down-regulation was enhanced when MLN8054 was applied simultaneously. In conclusion, our data demonstrate that targeting the proteasome and Aurora kinases simultaneously results in additional antitumoral effects in vitro, especially regarding cell growth and induction of apoptosis. The efficacy of this therapeutic approach remains to be revised by in vivo and clinical application.
传统的手术、放射性碘和甲状腺素抑制治疗往往无法治愈间变性甲状腺癌（ATC）。因此，人们尝试了几种新的治疗方法，包括使用“小分子抑制剂”。体外和异种移植肿瘤细胞研究表明，ATC 对单药蛋白酶体和 Aurora 激酶抑制有反应。本研究旨在评估硼替佐米和 Aurora 激酶联合靶向泛素-蛋白酶体系统治疗的效果，使用 MLN8054。使用三种 ATC 细胞系（Hth74、C643 和 Kat4.1）。通过 MTT 测定和细胞周期分析（FACS）评估联合治疗硼替佐米和 MLN8054 的抗增殖作用。通过测定 Caspase-3 活性评估促凋亡作用，并通过 ELISA 分析对 VEGF 分泌的影响。与单药应用相比，联合应用硼替佐米和 MLN8054 可进一步降低细胞密度，而细胞周期进展则存在拮抗作用。单药应用 MLN8054 和硼替佐米分别使 Caspase-3 活性增加 2.7 倍和 14 倍。当两种药物联合使用时，根据细胞系的不同，Caspase-3 活性进一步增强。硼替佐米治疗可降低 VEGF 分泌，而 MLN8054 治疗则保持不变。仅在 C643 细胞中，当同时应用 MLN8054 时，硼替佐米诱导的下调作用增强。总之，我们的数据表明，同时靶向蛋白酶体和 Aurora 激酶在体外可产生额外的抗肿瘤作用，特别是在细胞生长和诱导凋亡方面。这种治疗方法的疗效仍有待于体内和临床应用的验证。
