PMID- 34178653
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210629
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 11
DP  - 2021
TI  - The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor 
      PQR620.
PG  - 669518
LID - 10.3389/fonc.2021.669518 [doi]
LID - 669518
AB  - In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target 
      of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 
      is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential 
      activity in NSCLC cells. In primary human NSCLC cells and established cell lines 
      (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle 
      progression, as well as cell migration and invasion, while inducing significant 
      apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) 
      and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 
      phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a 
      constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced 
      cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC 
      cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, 
      PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and 
      oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily 
      oral administration of a single dose of PQR620 potently inhibited primary NSCLC 
      xenograft growth in severe combined immune deficient mice. In PQR620-treated 
      xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition 
      and oxidative stress were detected. In conclusion, PQR620 exerted potent 
      anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.
CI  - Copyright (c) 2021 Zha, Xia, Ye, Hu, Zhang, Xiao, Yu, Xu and Xu.
FAU - Zha, Jian-Hua
AU  - Zha JH
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Xia, Ying-Chen
AU  - Xia YC
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Ye, Chun-Lin
AU  - Ye CL
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Hu, Zhi
AU  - Hu Z
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Zhang, Qin
AU  - Zhang Q
AD  - Department of Respiratory Medicine, Suzhou Hospital Affiliated Nanjing Medical 
      University, Suzhou, China.
FAU - Xiao, Han
AU  - Xiao H
AD  - Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, China.
FAU - Yu, Ben-Tong
AU  - Yu BT
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Xu, Wei-Hua
AU  - Xu WH
AD  - Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow 
      University, Suzhou, China.
FAU - Xu, Guo-Qiu
AU  - Xu GQ
AD  - Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang 
      University, Nanchang, China.
LA  - eng
PT  - Journal Article
DEP - 20210610
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC8222575
OTO - NOTNLM
OT  - Akt
OT  - PQR620
OT  - mammalian target of rapamycin
OT  - non-small-cell lung carcinoma
OT  - signalings
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest. The reviewer CC declared a shared affiliation with one of 
      the authors WX to the handling editor at the time of the review.
EDAT- 2021/06/29 06:00
MHDA- 2021/06/29 06:01
PMCR- 2021/01/01
CRDT- 2021/06/28 06:04
PHST- 2021/02/19 00:00 [received]
PHST- 2021/05/11 00:00 [accepted]
PHST- 2021/06/28 06:04 [entrez]
PHST- 2021/06/29 06:00 [pubmed]
PHST- 2021/06/29 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2021.669518 [doi]
PST - epublish
SO  - Front Oncol. 2021 Jun 10;11:669518. doi: 10.3389/fonc.2021.669518. eCollection 
      2021.