BH3模拟药物ABT-737可诱导甲状腺癌细胞凋亡，并与化疗药物协同作用。
The BH3 mimetic drug ABT-737 induces apoptosis and acts synergistically with chemotherapeutic drugs in thyroid carcinoma cells.
作者信息
Broecker-Preuss Martina, Becher-Boveleth Nina, Müller Stefan, Mann Klaus
机构信息
Department of Endocrinology and Metabolism, Division of Laboratory Research, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany ; Department of Clinical Chemistry, University Hospital Essen, Hufelandstr. 55, Essen, Germany.
Department of Endocrinology and Metabolism, Division of Laboratory Research, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany ; Clinic of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, Essen, Germany.
出版信息
Cancer Cell Int. 2016 Apr 2;16:27. doi: 10.1186/s12935-016-0303-8. eCollection 2016.
BACKGROUND
Patients with dedifferentiated and anaplastic thyroid carcinomas that do not take up radioiodine are resistant to chemotherapeutic treatment and external irradiation and thus are difficult to treat. Direct induction of apoptosis is a promising approach in these apoptosis-resistant tumor cells. The BH3 mimetic ABT-737 belongs to a new class of drugs that target anti-apoptotic proteins of the BCL-2 family and facilitate cell death. The purpose of this study was to investigate the effect of ABT-737 alone or in combination with chemotherapeutic drugs on thyroid carcinoma cell lines.
METHODS
A total of 16 cell lines derived from follicular, papillary, and anaplastic thyroid carcinomas were treated with ABT-737. Cell viability was measured with MTT assay. Cell death was determined by cell cycle phase distribution and subG1 peak analyses, determination of caspase 3/7 activity and caspase cleavage products, lactate dehydrogenase (LDH) liberation assays and LC3 analysis by western blot.
RESULTS
The number of viable cells was decreased in all cell lines examined after ABT-737 treatment, with IC50 values ranging from 0.73 to 15.6 μM. Biochemical markers of apoptosis like caspase activities, caspase cleavage products and DNA fragmentation determined as SubG1 peak were elevated after ABT-737 treatment, but no LC3 cleavage was induced by ABT-737 indicating no autophagic processes. In combination with doxorubicin and gemcitabine, ABT-737 showed synergistic effects on cell viability.
CONCLUSIONS
With these experiments we demonstrated the efficacy of the BH3 mimetic drug ABT-737 against dedifferentiated thyroid carcinoma cells of various histological origins and showed synergistic effects with chemotherapeutic drugs. ABT-737-treated cells underwent an apoptotic cell death. ABT-737 and related BH3 mimetic drugs, alone or in combination, may thus be of value as a new therapeutic option for dedifferentiated thyroid carcinomas.
背景
去分化型和间变性甲状腺癌患者不摄取放射性碘，对化疗和外照射耐药，因此难以治疗。直接诱导凋亡是针对这些抗凋亡肿瘤细胞的一种有前景的方法。BH3模拟物ABT-737属于一类新型药物，可靶向BCL-2家族的抗凋亡蛋白并促进细胞死亡。本研究的目的是探讨ABT-737单独或与化疗药物联合应用对甲状腺癌细胞系的影响。
方法
用ABT-737处理16种来源于滤泡状、乳头状和间变性甲状腺癌的细胞系。用MTT法检测细胞活力。通过细胞周期阶段分布和亚G1峰分析、半胱天冬酶3/7活性和半胱天冬酶裂解产物的测定、乳酸脱氢酶（LDH）释放试验以及蛋白质免疫印迹法进行LC3分析来确定细胞死亡情况。
结果
ABT-737处理后，所有检测的细胞系中活细胞数量均减少，IC50值范围为0.73至15.6μM。ABT-737处理后，凋亡的生化标志物如半胱天冬酶活性、半胱天冬酶裂解产物以及作为亚G1峰测定的DNA片段化均升高，但ABT-737未诱导LC3裂解，表明无自噬过程。与多柔比星和吉西他滨联合应用时，ABT-737对细胞活力显示出协同作用。
结论
通过这些实验，我们证明了BH3模拟药物ABT-737对各种组织学来源的去分化甲状腺癌细胞有效，并与化疗药物显示出协同作用。经ABT-737处理的细胞发生凋亡性细胞死亡。因此，ABT-737及相关的BH3模拟药物单独或联合应用可能作为去分化甲状腺癌的一种新的治疗选择具有价值。
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