PI3K/Akt/mTOR通路抑制剂S1联合索拉非尼对小细胞肺癌的抗肿瘤作用研究  

Combination of S1,a novel PI3K/mTOR dual inhibitor,with sorafenib to treat small cell lung cancer

作　　者：王娟[1] 马淑梅[1] 陈秀华[1] 张三奇[2] 梅其炳[1] 

机构地区：[1]上海医药工业研究院药理评价研究中心,上海200437 [2]西安交通大学生命科学中心药学院药物化学部,西安710061

出　　处：《世界临床药物》2015年第11期752-758,共7页World Clinical Drug

摘　　要：目的探讨PI3K/Akt/m TOR通路新型抑制剂S1和Ras/Raf/MAPK抑制剂索拉非尼联合用于小细胞肺癌(SCLC)的抗肿瘤作用。方法通过体外增殖抑制试验、克隆形成试验、Transwell小室细胞侵袭试验和划痕试验,评价单独用药和联合用药对NCI-H446细胞的抑制作用。结果 S1作用24、48和72 h对NCI-H446细胞抑制作用的IC_50分别为92.82、23.19和1.79μmol/L,联用索拉非尼的IC_50分别为5.79、1.84和0.19μmol/L。药物作用72 h,所有联合组药物联合作用指数(CI)均小于1。克隆形成试验:0.4μmol/L S1+2μmol/L索拉非尼联合用药组抑制率为54.49%,克隆数与同剂量各单独给药组比较,差异均具有统计学意义(P<0.01);2μmol/L S1+2μmol/L索拉非尼联合用药组抑制率为72.46%,克隆数与索拉非尼2μmol/L组,比较差异具有统计学意义(P<0.01)。侵袭抑制试验:2μmol/L S1+4μmol/L索拉非尼联合用药组对NCI-H446细胞的抑制率高达76.84%,侵袭数与同等剂量单独给药组比较差异,均具有统计学意义(P<0.01)。迁移抑制试验:作用10 h,2μmol/L S1+4μmol/L索拉非尼联合用药对细胞的抑制率为95.15%,划痕距离显著大于索拉非尼4μmol/L组(P<0.01)。作用24 h,联合用药组抑制率为89.18%,划痕距离仍显著大于索拉非尼4μmol/L组(P<0.01)。结论 S1具有抗SCLC NCI-H446的作用,且与索拉非尼联合用药具有协同作用。Objective To evaluate the in vitro effects of a PI3K/mTOR dual inhibitor S1 alone or in combination with the multi-kinase inhibitor sorafenib on NCI-H446 SCLC cells. Methods The efficacy of S 1 alone or in combination with sorafenib in NCI-H446 were evaluated through anti-proliferation assay, colony formation assay, transwell invasion assay, and wound healing assay. Results The NCI-H446 cells treated with S 1 in 24, 48 and 72 h, resulted in reduced tumor cell proliferation with IC50 of 92.82, 23.29 and 1.79 μmol/L respectively. The combination group of S1 and sorafenib showed more reduction of tumor cells with the IC50of 5.79, 1.84 and 0.19 μmol/L. 2 and 0.4 μmol/L of S1 induced the inhibitions on colony formation with the IR% （inhibition rate） of 42.51%, 14.37%. After combining with sorafenib, the IR% reached 72.46% and 54.49%. 4 and 2 gmol/L of S1 restrained the NCI-H446 cells invasion with the IR% of 56.32% and 42.63%, 2 μmol/L S1 and sorafenib reached the IR% of 76.84%. After treated with 4 and 2 μmol/L of S1, the IR of wound healing were 83.01% and 69.35%, and the combination group with S1 and sorafenib reached 89.18%. Conclusion S1 has a good efficacy against NCI-H446 tumor, which can be enhanced by combination with sorafenib.

关 键 词：小细胞肺癌(SCLC) PI3K/Akt/m TOR通路抑制剂 索拉非尼 抗肿瘤药物 

分 类 号：R734.2[医药卫生—肿瘤] R979.1[医药卫生—临床医学]