Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells
Molecular mechanisms of the effects of low concentrations of taxol in anaplastic thyroid cancer cells
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DOI：
10.1210/en.2004-0127
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发表时间：
2004-07-01
期刊：
影响因子：
4.8
通讯作者：
Yamashita, S
中科院分区：
文献类型：
--
作者：
Pushkarev, VM;Starenki, DV;Yamashita, S
了解化疗药物对癌细胞作用的详细机制对于规划临床应用至关重要，因为药物作用通常具有组织和细胞类型特异性。本研究以ARO、KTC-2、KTC-3（甲状腺未分化癌）和FRO（未分化滤泡癌）四种细胞系和原代甲状腺细胞为实验模型，阐明泰素在人甲状腺未分化癌细胞中作用的分子途径。所有细胞系对紫杉醇敏感，但程度不同。在原代甲状腺细胞中，药物显示出显著较低的细胞毒性。在甲状腺癌细胞中，紫杉醇诱导的凋亡特征性变化，如聚（ADP-核糖）聚合酶和半胱氨酸蛋白酶原裂解和膜不对称性的改变，仅在6至50 nM的窄浓度范围内。在较高浓度下，观察到可能与线粒体崩溃相关的其他形式的细胞死亡。低剂量的紫杉醇增强Bcl 2磷酸化，并导致其降解的背景下观察到的Bax水平持续或增加和积累的生存素和X染色体连锁的细胞凋亡抑制剂。c-jun-NH 2末端激酶的激活是甲状腺未分化癌细胞凋亡的关键，而Raf/MAPK激酶/ERK和磷脂酰肌醇-3-OH激酶/Akt可能是主要的生存机制。我们的研究结果表明，在实验室研究中谨慎解释紫杉醇的生物学效应，并确定最佳剂量的紫杉醇，以达到预期的治疗效果，在甲状腺未分化癌的重要性。
Understanding the detailed mechanisms of a chemotherapeutic agent action on cancer cells is essential for planning the clinical applications because drug effects are often tissue and cell type specific. This study set out to elucidate the molecular pathways of Taxol effects in human anaplastic thyroid cancer cells using as an experimental model four cell lines, ARO, KTC-2, KTC-3 (anaplastic thyroid cancer), and FRO (undifferentiated follicular cancer), and primary thyrocytes. All cell lines were sensitive to Taxol, although to different extent. In primary thyrocytes the drug displayed substantially lower cytotoxicity. In thyroid cancer cells, Taxol-induced changes characteristic to apoptosis such as poly (ADP-ribose) polymerase and procaspase cleavage and alteration of membrane asymmetry only within a narrow concentration range, from 6 to 50 nM. At higher concentration, other form(s) of cell death perhaps associated with mitochondrial collapse was observed. Low doses of Taxol enhanced Bcl2 phosphorylation and led to its degradation observed on the background of a sustained or increasing Bax level and accumulation of survivin and X-chromosome-linked inhibitor of apoptosis. c-jun-NH2 terminal kinase activation was essential for the apoptosis in anaplastic thyroid cancer cells, whereas Raf/MAPK kinase/ERK and phosphatidylinositol-3-OH kinase/Akt were likely to comprise main survival mechanisms. Our results suggest an importance of cautious interpreting of biological effects of Taxol in laboratory studies and for determining optimal doses of Taxol to achieve the desired therapeutic effect in anaplastic thyroid cancers.