Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1
Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1
复制标题
阿托伐他汀通过抑制 AKT 激活和上调 TIMP-1 使人非小细胞肺癌对卡铂敏感
DOI：
10.1016/j.biocel.2012.01.015
复制
发表时间：
2012-05-01
影响因子：
4
通讯作者：
Li, Xuejun
中科院分区：
文献类型：
--
作者：
Chen, Jie;Lan, Tian;Li, Xuejun
铂类化疗是晚期非小细胞肺癌（NSCLC）的标准治疗。然而，由于AKT通路介导的卡铂在NSCLC治疗中不敏感，因此卡铂在NSCLC治疗中的抗肿瘤效果不令人满意。既往研究表明他汀类药物具有抗肿瘤活性，但阿托伐他汀能否逆转肺癌卡铂耐药尚不清楚。阿托伐他汀和卡铂联合治疗能减少裸鼠A549移植瘤的生长，并提高其生存率。阿托伐他汀联合卡铂对NSCLC的生长抑制和细胞凋亡的作用强于单独使用。卡铂在NSCLC细胞中主要通过抑制AKT活性和由此产生的TIMP-1上调来赋予抗侵袭作用。然而，卡铂对AKT活性的抑制作用是短期的。额外的阿托伐他汀给药通过在体内和体外更强和持久地抑制AKT活性，与卡铂协同抑制NSCLC细胞侵袭和刺激TIMP-1表达。使用另一种人肺癌细胞系（H1299）证实了阿托伐他汀和卡铂的协同作用。总而言之，我们的数据表明，阿托伐他汀可以通过抑制AKT活性和上调TIMP-1来克服肺癌的卡铂耐药性。阿托伐他汀联合卡铂可能是临床治疗NSCLC的有效策略。(c)2012爱思唯尔有限公司保留所有权利。
Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung carcinomas (NSCLCs). However, the antitumoral effect of carboplatin displays unsatisfactory in NSCLCs treatment due to the AKT pathway-mediated carboplatin insensitive in NSCLCs treatment. Previous studies have shown that statins have antitumor activity, but it is unknown whether atorvastatin can reverse carboplatin resistance in lung cancer. Treatment with atorvastatin and carboplatin reduced the growth of xenograft A549 tumors in nude mice and enhanced the survival rate compared with carboplatin alone. Atorvastatin in combination with carboplatin had stronger effects on growth inhibition and apoptosis of NSCLC than either agent used individually. Carboplatin conferred anti-invasive effect in NSCLC cells mainly through inhibition of AKT activity and resultant upregulation of TIMP-1. However, the inhibitory effect on AKT activity by carboplatin was short-term. Additional atorvastatin administration resulted in synergistic inhibition of NSCLC cell invasion and stimulation of TIMP-1 expression with carboplatin through stronger and persistent inhibition of AKT activity both in vivo and in vitro. The synergy of atorvastatin and carboplatin was confirmed using another human lung carcinoma cell line (H1299). Altogether, our data demonstrate that atorvastatin may overcome carboplatin resistance in lung cancer by suppressing AKT activity and upregulating TIMP-1. A combination of atorvastatin and carboplatin may be an effective strategy in clinical therapy against NSCLCs. (c) 2012 Elsevier Ltd. All rights reserved.