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

Sun Z, Li Q, Zhang S, Chen J, Huang L, Ren J, Chang Y, Liang Y, Wu G - Onco Targets Ther (2015)

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

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

BEZ235 combination with gefitinib reduced VEGF and CD31 expression in vivo.Note: Immunohistochemistry of CD31 and VEGF was performed for tumors treated with gefitinib, BEZ235, and their combination.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; CD, cluster of differentiation; GEF, gefitinib; VEGF, vascular endothelial growth factor.
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f5-ott-8-269: BEZ235 combination with gefitinib reduced VEGF and CD31 expression in vivo.Note: Immunohistochemistry of CD31 and VEGF was performed for tumors treated with gefitinib, BEZ235, and their combination.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; CD, cluster of differentiation; GEF, gefitinib; VEGF, vascular endothelial growth factor.

Mentions: Aberrant PI3K signaling impairs phosphatase and tensin homologue function, which plays an important part in tumor angiogenesis and in normal vascular formation.22,23 Therefore, we examined whether BEZ235 could interfere with tumor angiogenesis in nude mice xenografts. Immunohistochemical detection showed a significant reduction in VEGF and CD31 staining in BEZ235-treated tumors as compared with the controls (Figure 5), suggesting that BEZ235 may be involved in the inhibition of tumor angiogenesis.


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

Sun Z, Li Q, Zhang S, Chen J, Huang L, Ren J, Chang Y, Liang Y, Wu G - Onco Targets Ther (2015)

BEZ235 combination with gefitinib reduced VEGF and CD31 expression in vivo.Note: Immunohistochemistry of CD31 and VEGF was performed for tumors treated with gefitinib, BEZ235, and their combination.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; CD, cluster of differentiation; GEF, gefitinib; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4321659&req=5

f5-ott-8-269: BEZ235 combination with gefitinib reduced VEGF and CD31 expression in vivo.Note: Immunohistochemistry of CD31 and VEGF was performed for tumors treated with gefitinib, BEZ235, and their combination.Abbreviations: B+G, NVP-BEZ235 combination with gefitinib; BEZ, NVP-BEZ235; BLK, blank control; CD, cluster of differentiation; GEF, gefitinib; VEGF, vascular endothelial growth factor.
Mentions: Aberrant PI3K signaling impairs phosphatase and tensin homologue function, which plays an important part in tumor angiogenesis and in normal vascular formation.22,23 Therefore, we examined whether BEZ235 could interfere with tumor angiogenesis in nude mice xenografts. Immunohistochemical detection showed a significant reduction in VEGF and CD31 staining in BEZ235-treated tumors as compared with the controls (Figure 5), suggesting that BEZ235 may be involved in the inhibition of tumor angiogenesis.

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

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus