PMID- 32236634
OWN - NLM
STAT- MEDLINE
DCOM- 20210122
LR  - 20210915
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 56
IP  - 6
DP  - 2020 Jun
TI  - HS‑146, a novel phosphoinositide 3‑kinase alpha inhibitor, induces the apoptosis and 
      inhibits the metastatic ability of human breast cancer cells.
PG  - 1509-1520
LID - 10.3892/ijo.2020.5018 [doi]
AB  - 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 PI3Kalpha 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 3beta (GSK3beta), p70S6K1 and eukaryotic translation initiation factor 
      4E‑binding protein 1 (4E‑BP1). Hypoxia‑inducible factor (HIF)‑1alpha 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 PI3Kalpha inhibitor, may be an effective 
      novel therapeutic candidate that suppresses breast cancer proliferation and 
      metastasis by inhibiting the PI3K/Akt/mTOR pathway.
FAU - Kim, Ok Hyeon
AU  - Kim OH
AD  - College of Korean Medicine, Dongguk University, Goyang, Gyeonggi 10326, Republic 
      of Korea.
FAU - Lee, Ju-Hee
AU  - Lee JH
AD  - College of Korean Medicine, Dongguk University, Goyang, Gyeonggi 10326, Republic 
      of Korea.
FAU - Mah, Shinmee
AU  - Mah S
AD  - Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science 
      (IBS), Daejeon 34141, Republic of Korea.
FAU - Park, Sung Yun
AU  - Park SY
AD  - College of Korean Medicine, Dongguk University, Goyang, Gyeonggi 10326, Republic 
      of Korea.
FAU - Hong, Sungwoo
AU  - Hong S
AD  - Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science 
      (IBS), Daejeon 34141, Republic of Korea.
FAU - Hong, Soon-Sun
AU  - Hong SS
AD  - Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 
      22332, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20200319
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Sulfonamides)
SB  - IM
MH  - Breast Neoplasms/drug therapy/*metabolism
MH  - Cell Cycle Proteins/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - MCF-7 Cells
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - Phosphoinositide-3 Kinase Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Sulfonamides/chemical synthesis/chemistry/*pharmacology
OTO - NOTNLM
OT  - phosphoinositide 3-kinase alpha inhibitor
OT  - HS-146
OT  - proliferation
OT  - apoptosis
OT  - cell cycle
OT  - hypoxia
OT  - migration
OT  - invasion
EDAT- 2020/04/03 06:00
MHDA- 2021/01/23 06:00
CRDT- 2020/04/03 06:00
PHST- 2019/08/28 00:00 [received]
PHST- 2020/02/21 00:00 [accepted]
PHST- 2020/04/03 06:00 [pubmed]
PHST- 2021/01/23 06:00 [medline]
PHST- 2020/04/03 06:00 [entrez]
AID - 10.3892/ijo.2020.5018 [doi]
PST - ppublish
SO  - Int J Oncol. 2020 Jun;56(6):1509-1520. doi: 10.3892/ijo.2020.5018. Epub 2020 Mar 
      19.