摘要
目的探讨多激酶抑制剂索拉非尼单药及与二甲双胍联合给药时，对甲状腺未分化癌细胞的作用及其机制。方法采用细胞培养技术，以流式细胞术、Western印迹等方法．在索拉非尼单药或与二甲双胍联合给药后，观察细胞生长、细胞周期及凋亡、easpase一3活性以及细胞外信号调节激酶（ERK）磷酸化的变化。结果索拉非尼抑制甲状腺未分化癌细胞生长，干预48h后，索拉非尼对SWl736和C643的Ec。分别为3．68Ixmol／L和4．87Ixmol／L；阻断细胞周期于G0／1期，s期细胞显著减少；诱导细胞凋亡，索拉非尼、索拉非尼＋二甲双胍作用后，SWl736细胞caspase3活性分别为131．5％、278．0％（P〈0．01），C643细胞caspase3活性分别为127．2％、196．6％（P〈0．01）。分子水平，索拉非尼抑制ERK蛋白磷酸化。二甲双胍可协同索拉非尼抑制肿瘤细胞生长，2．5μmol／L索拉非尼、2．5txmol／L索拉非尼＋5mmol／L二甲双胍作用后，SWl736细胞活力为0．76±0．17、0．30±0．04（P〈0．01）。C643分别为0．72±0．09、0．34±0．10（P〈0．001）。结论多激酶抑制剂索拉非尼和二甲双胍联合用药可成为临床上治疗甲状腺未分化癌及其他进展期肿瘤的有效策略。
Objective To elucidate the effect of muhi-kinase inhibitor sorafenib on anaplastic thyroid carcinoma cells in the presence or absence of mefformin. Methods SW1736 and C643 cells were treated with sorafenib in the presence or absence of metformin for various periods of time. Cell viability was detected by MTT. Cell cycle and cell apoptosis were measured by flow cytometry. Caspase-3 activity was detected by eolorimetric kit. Western blot was used to analyze pERK phosphorylation and cyclinD1 expression. Results Sorafenib inhibited the growth of anaplastic thyroid carcinoma cells and induced cell cycle arrest and cell apoptosis. The ECs0 of sorafenib in SW1736 and C643 was 3.68μmoL/L and 4.87 μmol/L respectively. After sorafenib metformin treatment, the easpase3 activity was 131.5% and 278.0% （ P〈0.01 ） in SW1736 cells, 127.2% and 196.6% （ P〈0.01 ） in C643 cells. On the molecular level, sorafenib inhibited the phosphorylation of ERK and decreased the expression of cyelinD1. Metformin amplified the growth inhibitory effect of sorafenib on anaplastic thyroid carcinoma cells. The cell viability was 0.76 ± 0.17 and 0.30 ± 0.04 （ P〈0.01 ） in SW1736 cells, 0.72 ± 0.09 and 0.34 ± 0.10 （ P〈0. 001 ） in C643 cells after 2.5 p, mol/L sorafenib without or with 5 mmol/L metformin treatment. Conclusions The combination of sorafenib and metformin may be a potent strategy for the treatment of anaplastic thyroid carcinoma and other advanced cancers.
出处
《中华内分泌代谢杂志》
CAS
CSCD
北大核心
2013年第7期608-612,共5页
Chinese Journal of Endocrinology and Metabolism
基金
国家自然科学基金资助项目（81200577）
