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已发表论文
顺利获得下调 PI3K/AKT/ mTOR 的磷酸化，NVP-BEZ235 克服吉非替尼的取得性耐药
Authors Sun ZH, Li QH, Zhang S, Chen J, Huang LL, Ren JH, Chang Y, Liang YC, Wu G
Published Date January 2015 Volume 2015:8 Pages 269—277
DOI http://dx.doi.org/10.2147/OTT.S62128
Received 8 February 2014, Accepted 16 May 2014, Published 29 January 2015
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.
Keywords: gefitinib-acquired resistance, PI3K kinase, mTOR, NVP-BEZ235
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.
Keywords: gefitinib-acquired resistance, PI3K kinase, mTOR, NVP-BEZ235
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