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PI3K-targeting strategy using alpelisib to enhance the antitumor effect of paclitaxel in human gastric cancer
- Source :
- Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020), Scientific Reports
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- PIK3CA mutations are frequently observed in various human cancers including gastric cancer (GC). This study was conducted to investigate the anti-tumor effects of alpelisib, a PI3K p110α-specific inhibitor, using preclinical models of GC. In addition, the combined effects of alpelisib and paclitaxel on GC were evaluated. Among the SNU1, SNU16, SNU484, SNU601, SNU638, SNU668, AGS, and MKN1 GC cells, three PIK3CA-mutant cells were predominantly sensitive to alpelisib. Alpelisib monotherapy decreased AKT and S6K1 phosphorylation and induced G0/G1 phase arrest regardless of PIK3CA mutational status. The alpelisib and paclitaxel combination demonstrated synergistic anti-proliferative effects, preferentially on PIK3CA-mutant cells, resulting in increased DNA damage response and apoptosis. In addition, alpelisib and paclitaxel combination potentiated anti-migratory activity in PIK3CA-mutant cells. Alpelisib partially reversed epithelial–mesenchymal transition markers in PIK3CA-mutant cells. In a xenograft model of MKN1 cells, the alpelisib and paclitaxel combination significantly enhanced anti-tumor activity by decreasing Ki-67 expression and increasing apoptosis. Moreover, this combination tended to prolong the survival of tumor-bearing mice. Our data suggest promising anti-tumor efficacy of alpelisib alone or in combination with paclitaxel in PIK3CA-mutant GC cells.
- Subjects :
- Epithelial-Mesenchymal Transition
Paclitaxel
DNA damage
Mice, Nude
lcsh:Medicine
Apoptosis
P70-S6 Kinase 1
Article
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Cell Movement
Stomach Neoplasms
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
lcsh:Science
neoplasms
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
Phosphoinositide-3 Kinase Inhibitors
Cancer
Multidisciplinary
Molecular medicine
Chemistry
Cell Cycle
lcsh:R
Cell Cycle Checkpoints
medicine.disease
Xenograft Model Antitumor Assays
Thiazoles
Cell culture
Caspases
Mutation
Cancer research
Female
lcsh:Q
DNA Damage
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....c72a74374b92db267fd954aba35af598