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NVP-BEZ235通过下调PI3K/AKT/mTOR磷酸化来克服吉非替尼获得性耐药。

NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation.

作者信息

Sun Zhihua, Li Qiuhui, Zhang Sheng, Chen Jing, Huang Lili, Ren Jinghua, Chang Yu, Liang Yichen, Wu Gang

机构信息

Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People's Republic of China.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.

出版信息

Onco Targets Ther. 2015 Jan 29;8:269-77. doi: 10.2147/OTT.S62128. eCollection 2015.

DOI:10.2147/OTT.S62128
PMID:25674002
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4321659/
Abstract

BACKGROUND

Patients harboring activating mutations in epidermal growth factor receptors (EGFR) are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), in gefitinib-resistant non-small cell lung cancer.

METHODS

H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT)/mTOR signaling pathway proteins.

RESULTS

We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins.

CONCLUSION

Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.

摘要

背景

携带表皮生长因子受体（EGFR）激活突变的患者对EGFR酪氨酸激酶抑制剂（TKIs）特别敏感。然而，大多数患者在大约10个月后会产生获得性耐药。本研究聚焦于磷脂酰肌醇-3-激酶/哺乳动物雷帕霉素靶蛋白（PI3K/mTOR）双重抑制剂NVP-BEZ235对吉非替尼耐药的非小细胞肺癌的治疗效果。

方法

通过核苷酸序列分析验证H1975细胞系为吉非替尼耐药细胞模型。我们使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法检测H1975细胞系的体外生长情况。通过迁移实验检测H1975细胞的迁移。采用异种移植模型研究吉非替尼耐药的非小细胞肺癌在体内的生长情况。使用蛋白质免疫印迹法和免疫组织化学分析法研究PI3K/蛋白激酶B（AKT）/mTOR信号通路蛋白的水平。

结果

我们发现NVP-BEZ235在体内和体外均能有效抑制H1975细胞的生长。同样，NVP-BEZ235可减少H1975细胞的迁移。进一步实验表明，NVP-BEZ235可减弱PI3K/AKT/mTOR信号通路蛋白的磷酸化。

结论

综上所述，我们认为NVP-BEZ235通过下调PI3K/AKT/mTOR磷酸化来抑制吉非替尼耐药肿瘤的生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/4b60481bc300/ott-8-269Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/c5eec9ba8dbe/ott-8-269Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/b45d03c08094/ott-8-269Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/1ab7268172be/ott-8-269Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/49e55d342583/ott-8-269Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/4b60481bc300/ott-8-269Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/c5eec9ba8dbe/ott-8-269Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/b45d03c08094/ott-8-269Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/1ab7268172be/ott-8-269Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/49e55d342583/ott-8-269Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/38c1/4321659/4b60481bc300/ott-8-269Fig5.jpg

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