PMID- 37424807
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230718
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 13
IP  - 6
DP  - 2023
TI  - Therapeutic potential of EGFR/mTOR/Nf-kb targeting small molecule for the 
      treatment of non-small cell lung cancer.
PG  - 2598-2616
AB  - Despite the therapeutic advancement with chemotherapy and targeted therapy 
      against non-small-cell lung cancer (NSCLC), most patients ultimately develop 
      resistance to these drugs, exhibiting disease progression, metastasis, and worse 
      prognosis. There is, therefore, a need for the development of novel 
      multi-targeted therapies that can offer a high therapeutic index with lesser 
      chances of drug resistance against NSCLC. In the present study, we evaluated the 
      therapeutic potential of a novel multi-target small molecule NLOC-015A for 
      targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A 
      exhibited a broad spectrum of anticancer activities against lung cancer cell 
      line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective 
      IC(50) values of 2.07+/-0.19 and 1.90+/-0.23 microm. In addition, NLOC-015A attenuated 
      the oncogenic properties (colony formation, migratory ability, and spheroid 
      formation) with concomitant downregulation of expression levels of epidermal 
      growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear 
      factor (NF)-kappaB, signaling network. In addition, the stemness inhibitory effect of 
      NLOC0-15A was accompanied by decreased expression levels of aldehyde 
      dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region 
      Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A 
      suppressed the tumor burden and increased the body weight and survival of H1975 
      xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and 
      hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A 
      synergistically enhanced the in vitro efficacy, and therapeutic outcome of 
      osimertinib in vivo. In addition, the toxicity of osimertinib was significantly 
      attenuated by combination with NLOC-015A. Altogether, our findings suggested that 
      combining osimertinib with NLOC-015 appears to be a promising way to improve 
      osimertinib's efficacy and achieve better therapeutic results against NSCLC. We 
      therefore suggest that NLOC-015A might represent a new candidate for treating 
      NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Kappab signaling networks 
      and efficiently compromising the oncogenic phenotype of NSCLC.
CI  - AJCR Copyright (c) 2023.
FAU - Lawal, Bashir
AU  - Lawal B
AD  - UPMC Hillman Cancer Center, University of Pittsburgh Pittsburgh, PA 15260, USA.
AD  - Department of Pathology, University of Pittsburgh Pittsburgh, PA 15260, USA.
FAU - Kuo, Yu-Cheng
AU  - Kuo YC
AD  - Department of Pharmacology, School of Medicine, College of Medicine, Taipei 
      Medical University Taipei 11031, Taiwan.
AD  - School of Post-baccalaureate Chinese Medicine, College of Chinese Medicine, China 
      Medical University Taichung 40402, Taiwan.
FAU - Wu, Alexander Th
AU  - Wu AT
AD  - The PhD Program of Translational Medicine, College of Medical Science and 
      Technology, Taipei Medical University Taipei 11031, Taiwan.
AD  - Clinical Research Center, Taipei Medical University Hospital, Taipei Medical 
      University Taipei 11031, Taiwan.
AD  - TMU Research Center of Cancer Translational Medicine, Taipei Medical University 
      Taipei 11031, Taiwan.
AD  - Graduate Institute of Medical Sciences, National Defense Medical Center Taipei 
      11490, Taiwan.
FAU - Huang, Hsu-Shan
AU  - Huang HS
AD  - Graduate Institute of Medical Sciences, National Defense Medical Center Taipei 
      11490, Taiwan.
AD  - PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical 
      Science and Technology, Taipei Medical University and Academia Sinica Taipei 
      11031, Taiwan.
AD  - Graduate Institute for Cancer Biology and Drug Discovery, College of Medical 
      Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
AD  - School of Pharmacy, National Defense Medical Center Taipei 11490, Taiwan.
AD  - PhD Program in Drug Discovery and Development Industry, College of Pharmacy, 
      Taipei Medical University Taipei 11031, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20230615
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC10326574
OTO - NOTNLM
OT  - NLOC-15A
OT  - epidermal growth factor receptor (EGFR)
OT  - non-small-cell lung cancer (NSCLC)
OT  - small molecule
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.
EDAT- 2023/07/10 06:42
MHDA- 2023/07/10 06:43
PMCR- 2023/06/15
CRDT- 2023/07/10 04:48
PHST- 2023/04/05 00:00 [received]
PHST- 2023/05/28 00:00 [accepted]
PHST- 2023/07/10 06:43 [medline]
PHST- 2023/07/10 06:42 [pubmed]
PHST- 2023/07/10 04:48 [entrez]
PHST- 2023/06/15 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2023 Jun 15;13(6):2598-2616. eCollection 2023.