Synergistic effects of sorafenib in combination with gemcitabine or pemetrexed in lung cancer cell lines with K-ras mutations
Synergistic effects of sorafenib in combination with gemcitabine or pemetrexed in lung cancer cell lines with K-ras mutations
复制标题
索拉非尼联合吉西他滨或培美曲塞对 K-ras 突变肺癌细胞系的协同作用
DOI：
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Yuan Yuan
中科院分区：
文献类型：
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作者：
Jing Li;S. Wang;Zengfeng Su;Yuan Yuan
K-ras是目前公认的非小细胞肺癌（NSCLC，包括鳞状细胞癌、腺癌和大细胞癌）中最常见的突变癌基因。具有K-ras突变的非小细胞肺癌患者似乎对大多数全身治疗都难治。在本研究中，索拉非尼联合吉西他滨或培美曲塞在K-ras突变阳性的NSCLC A549细胞系中的体外抗肿瘤作用和相关的分子机制进行了探索。索拉非尼在A549细胞中表现出剂量依赖性生长抑制，而索拉非尼联合培美曲塞与索拉非尼联合吉西他滨相比表现出更大的协同作用。索拉非尼将细胞周期阻滞在G1期，而吉西他滨和培美曲塞将细胞周期阻滞在S期。这种协同作用的分子机制是由于下游信号传导途径，索拉非尼有效地抑制了这些信号传导途径，因此增加了化疗药物进入凋亡途径的发生率。此外，索拉非尼和培美曲塞表现出更强的协同作用，表明同时抑制Ras/Raf/Mek/Erk和Ras/PI 3 K/Akt通路可实现改善的抗肿瘤作用。
K-ras is currently accepted as the most frequently mutated oncogene in non-small cell lung cancer (NSCLC, including squamous carcinoma, adenocarcinoma, and large cell carcinoma). NSCLC patients with the K-ras mutation appear to be refractory to the majority of systemic therapies. In the present study, the in vitro antitumor effects and correlated molecular mechanisms of sorafenib combined with gemcitabine or pemetrexed were explored in the K-ras mutation-positive NSCLC A549 cell line. Sorafenib was seen to exhibit dose-dependent growth inhibition in the A549 cells, while sorafenib combined with pemetrexed demonstrated a greater synergism compared with sorafenib combined with gemcitabine. Sorafenib arrested the cell cycle at the G1 phase, while gemcitabine and pemetrexed caused arrest at the S phase. The molecular mechanism of this synergism was due to the downstream signalling pathways, which were efficiently suppressed by sorafenib, therefore increasing the incidence of the entry of the chemotherapeutic drugs into the apoptotic pathways. Moreover, sorafenib and pemetrexed demonstrated stronger synergism, demonstrating that inhibiting the Ras/Raf/Mek/Erk and Ras/PI3K/Akt pathways concurrently may achieve improved antitumor effects.
影响因子：
11.2
作者：
K. Torres;S. B. Horwitz
通讯作者：
K. Torres;S. B. Horwitz