Department of Radiation Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Thyroid. 2012 Jul;22(7):717-24. doi: 10.1089/thy.2011.0380. Epub 2012 May 31.
We previously reported the partial effectiveness of imatinib (also known as STI571, Glivec, or Gleevec) on anaplastic thyroid cancer (ATC) cells. Imatinib is a selective tyrosine kinase inhibitor that has been used for various types of cancer treatments. Recently, several reports have demonstrated that imatinib enhanced the sensitivity of cancer cells to other anticancer drugs. In this study, therefore, we investigated whether imatinib enhances the antitumor activity of docetaxel in ATC cells.
Two ATC cell lines, FRO and KTC-2, were treated with imatinib and/or docetaxel. Cell survival assay and flow cytometry for annexin V were used to assess the induction of apoptosis. Changes of pro- and antiapoptotic factors were determined by Western blot. Nuclear factor-κB (NF-κB) activity was measured by DNA-binding assay. Tumor growth was also investigated in vivo.
The combined treatment significantly enhanced apoptosis compared with single treatment. ATC cells themselves expressed high levels of antiapoptotic factors, X-linked inhibitor of apoptosis (XIAP), and survivin. The treatment with docetaxel alone further increased their expressions; however, the combined treatment blocked the inductions. Although imatinib alone had no effect on NF-κB background levels, combined treatment significantly suppressed the docetaxel-induced NF-κB activation. Further, the combined administration of the drugs also showed significantly greater inhibitory effect on tumor growth in mice xenograft model.
Imatinib enhanced antitumor activity of docetaxel in ATC cells. Docetaxel seemed to induce both pro- and antiapoptotic signaling pathways in ATC cells, and imatinib blocked the antiapoptotic signal. Thus, docetaxel combined with imatinib emerges as an attractive strategy for the treatment of ATC.
我们之前报道过伊马替尼（也称为 STI571、Glivec 或 Gleevec）对间变性甲状腺癌（ATC）细胞具有一定疗效。伊马替尼是一种选择性酪氨酸激酶抑制剂，已被用于多种癌症的治疗。最近，有几项报告表明伊马替尼增强了癌细胞对其他抗癌药物的敏感性。因此，在本研究中，我们研究了伊马替尼是否增强了 ATC 细胞中多西紫杉醇的抗肿瘤活性。
用伊马替尼和/或多西紫杉醇处理两种 ATC 细胞系 FRO 和 KTC-2。采用细胞存活测定和 Annexin V 流式细胞术评估细胞凋亡的诱导。通过 Western blot 检测促凋亡和抗凋亡因子的变化。通过 DNA 结合测定法测量核因子-κB（NF-κB）活性。还在体内研究了肿瘤生长。
与单一治疗相比，联合治疗显著增强了细胞凋亡。ATC 细胞本身表达高水平的抗凋亡因子，X 连锁凋亡抑制剂（XIAP）和生存素。单独用多西紫杉醇治疗进一步增加了它们的表达；然而，联合治疗阻断了诱导。尽管伊马替尼单独对 NF-κB 背景水平没有影响，但联合治疗显著抑制了多西紫杉醇诱导的 NF-κB 激活。此外，两种药物联合给药对小鼠异种移植模型中的肿瘤生长也表现出显著更强的抑制作用。
伊马替尼增强了 ATC 细胞中多西紫杉醇的抗肿瘤活性。多西紫杉醇似乎诱导了 ATC 细胞中的促凋亡和抗凋亡信号通路，而伊马替尼阻断了抗凋亡信号。因此，多西紫杉醇联合伊马替尼可能成为治疗 ATC 的一种有吸引力的策略。
