HS-146, a novel phosphoinositide 3-kinase α inhibitor, induces the apoptosis and inhibits the metastatic ability of human breast cancer cells
- Authors
- Kim O.H.; Lee J.-H.; Mah S.; Park S.Y.; Hong S.; Hong S.-S.
- Issue Date
- Jun-2020
- Publisher
- Spandidos Publications
- Keywords
- Apoptosis; Cell cycle; HS-146; Hypoxia; Invasion; Migration; Phosphoinositide 3-kinase α inhibitor; Proliferation
- Citation
- International Journal of Oncology, v.56, no.6, pp 1509 - 1520
- Pages
- 12
- Journal Title
- International Journal of Oncology
- Volume
- 56
- Number
- 6
- Start Page
- 1509
- End Page
- 1520
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/44486
- DOI
- 10.3892/ijo.2020.5018
- ISSN
- 1019-6439
1791-2423
- Abstract
- The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in human cancer as it regulates critical cellular functions, such as survival, proliferation and metabolism. In the present study, a novel PI3Kα inhibitor (HS-146) was synthesized and its anticancer effects on MCF-7, MDA-MB-231, SKBR3 and BT-474 human breast cancer cell lines were confirmed. HS-146 was found to be most effective in inhibiting the proliferation of MCF-7 cells and in inducing cell cycle arrest in the G0/G1 phase by downregulating cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)2 and Cdk4, and upregulating p21Waf1/Cip1 protein levels in this cell line. The induction of apoptosis by HS-146 was confirmed by DAPI staining and western blot analysis. Cell shrinkage and nuclear condensation, which are typical morphological markers of apoptosis, were increased by HS-146 in the MCF-7 cells in a concentration-dependent manner, and HS-146 also increased the protein expression levels of cleaved poly(ADP-ribose) polymerase (PARP) and decreased the protein expression levels of Mcl-1 and caspase-7. In addition, HS-146 effectively decreased the phosphorylation levels of downstream PI3K effectors, such as Akt, mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β), p70S6K1 and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) expression were also suppressed by HS-146 under hypoxic conditions, and HS-146 inhibited the migration and invasion of MCF-7 cells in a concentration-dependent manner. On the whole, the findings of the present study suggest that HS-146, a novel PI3Kα inhibitor, may be an effective novel therapeutic candidate that suppresses breast cancer proliferation and metastasis by inhibiting the PI3K/Akt/mTOR pathway. © 2020 Spandidos Publications. All rights reserved.
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