Limits...
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

H1975 cell migration was inhibited by BEZ235.Notes: H1975 cells were seeded in 24-well plates and incubated with different concentrations of drugs. After 24 hours incubation, migrated cells were stained. The results are from a representative experiment. Each experiment, repeated three times, yielded similar results. (A) The inhibitory effect of BEZ235 on H1975 cells’ migration was increased with BEZ235 concentration. (B) H1975 cells migration was inhibited by combined administration of BEZ235 and gefitinib.Abbreviations: BEZ, NVP-BEZ235; GEF, gefitinib.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4321659&req=5

f2-ott-8-269: H1975 cell migration was inhibited by BEZ235.Notes: H1975 cells were seeded in 24-well plates and incubated with different concentrations of drugs. After 24 hours incubation, migrated cells were stained. The results are from a representative experiment. Each experiment, repeated three times, yielded similar results. (A) The inhibitory effect of BEZ235 on H1975 cells’ migration was increased with BEZ235 concentration. (B) H1975 cells migration was inhibited by combined administration of BEZ235 and gefitinib.Abbreviations: BEZ, NVP-BEZ235; GEF, gefitinib.

Mentions: The inhibitory effect of BEZ235 on the migration of H1975 cells was examined by migration assay. Figure 2A shows cell migration was significantly inhibited by BEZ235 alone. The difference of the inhibitory effect between each group suggested that the inhibition acts in a dose-dependent manner. When administrated and combined with gefitinib, BEZ235 inhibited H1975 cell migration in the same manner, as seen in Figure 2B.


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)

H1975 cell migration was inhibited by BEZ235.Notes: H1975 cells were seeded in 24-well plates and incubated with different concentrations of drugs. After 24 hours incubation, migrated cells were stained. The results are from a representative experiment. Each experiment, repeated three times, yielded similar results. (A) The inhibitory effect of BEZ235 on H1975 cells’ migration was increased with BEZ235 concentration. (B) H1975 cells migration was inhibited by combined administration of BEZ235 and gefitinib.Abbreviations: BEZ, NVP-BEZ235; GEF, gefitinib.
© Copyright Policy
Related In: Results  -  Collection

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

f2-ott-8-269: H1975 cell migration was inhibited by BEZ235.Notes: H1975 cells were seeded in 24-well plates and incubated with different concentrations of drugs. After 24 hours incubation, migrated cells were stained. The results are from a representative experiment. Each experiment, repeated three times, yielded similar results. (A) The inhibitory effect of BEZ235 on H1975 cells’ migration was increased with BEZ235 concentration. (B) H1975 cells migration was inhibited by combined administration of BEZ235 and gefitinib.Abbreviations: BEZ, NVP-BEZ235; GEF, gefitinib.
Mentions: The inhibitory effect of BEZ235 on the migration of H1975 cells was examined by migration assay. Figure 2A shows cell migration was significantly inhibited by BEZ235 alone. The difference of the inhibitory effect between each group suggested that the inhibition acts in a dose-dependent manner. When administrated and combined with gefitinib, BEZ235 inhibited H1975 cell migration in the same manner, as seen in Figure 2B.

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