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.
Keywords: phosphoinositide 3-kinase α inhibitor; HS-146; proliferation; apoptosis; cell cycle; hypoxia; migration; invasion.