PMID- 23632475
OWN - NLM
STAT- MEDLINE
DCOM- 20130726
LR  - 20220331
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 108
IP  - 10
DP  - 2013 May 28
TI  - Metformin inhibits growth and enhances radiation response of non-small cell lung 
      cancer (NSCLC) through ATM and AMPK.
PG  - 2021-32
LID - 10.1038/bjc.2013.187 [doi]
AB  - BACKGROUND: We examined the potential of metformin (MET) to enhance non-small 
      cell lung cancer (NSCLC) responses to ionising radiation (IR). METHODS: Human 
      NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase 
      (AMPK) alpha1/2-subunit(-/-) embryos (AMPKalpha1/2(-/-)-MEFs) and NSCLC tumours grafted 
      into Balb/c-nude mice were treated with IR and MET and subjected to 
      proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and 
      immunohistochemistry (IHC). RESULTS: Metformin (2.5 muM-5 mM) inhibited 
      proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the 
      ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the 
      Akt-mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) 
      pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM 
      inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer 
      cells with inhibited AMPK and AMPKalpha1/2(-/-)-MEFs were resistant to the 
      antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft 
      growth and combined treatment enhanced it further than each treatment alone. 
      Ionising radiation and MET induced (i) sustained activation of 
      ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR-4EBP1 pathways in tumours, (ii) 
      reduced expression of angiogenesis and (iii) enhanced expression of apoptosis 
      markers. CONCLUSION: Clinically achievable MET doses inhibit NSCLC cell and 
      tumour growth and sensitise them to IR. Metformin and IR mediate their action 
      through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a 
      clinically useful adjunct to radiotherapy in NSCLC.
FAU - Storozhuk, Y
AU  - Storozhuk Y
AD  - Department of Research, Juravinski Cancer Center, 699 Concession Street, Hamilton 
      L8V 5C2, ON, Canada.
FAU - Hopmans, S N
AU  - Hopmans SN
FAU - Sanli, T
AU  - Sanli T
FAU - Barron, C
AU  - Barron C
FAU - Tsiani, E
AU  - Tsiani E
FAU - Cutz, J-C
AU  - Cutz JC
FAU - Pond, G
AU  - Pond G
FAU - Wright, J
AU  - Wright J
FAU - Singh, G
AU  - Singh G
FAU - Tsakiridis, T
AU  - Tsakiridis T
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130430
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (ATM protein, human)
RN  - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
RN  - EC 2.7.11.1 (Atm protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
SB  - IM
MH  - Adenylate Kinase/metabolism/*physiology
MH  - Animals
MH  - Ataxia Telangiectasia Mutated Proteins
MH  - Carcinoma, Non-Small-Cell Lung/metabolism/pathology/*radiotherapy
MH  - Cell Cycle Proteins/metabolism/*physiology
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/metabolism/*physiology
MH  - Down-Regulation/drug effects
MH  - Embryo, Mammalian
MH  - Humans
MH  - Lung Neoplasms/metabolism/pathology/*radiotherapy
MH  - Metformin/pharmacology/*therapeutic use
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Mice, Nude
MH  - Protein Serine-Threonine Kinases/metabolism/*physiology
MH  - Radiation-Sensitizing Agents/pharmacology/*therapeutic use
MH  - Tumor Suppressor Proteins/metabolism/*physiology
MH  - Xenograft Model Antitumor Assays
PMC - PMC3670487
EDAT- 2013/05/02 06:00
MHDA- 2013/07/28 06:00
PMCR- 2014/05/28
CRDT- 2013/05/02 06:00
PHST- 2013/05/02 06:00 [entrez]
PHST- 2013/05/02 06:00 [pubmed]
PHST- 2013/07/28 06:00 [medline]
PHST- 2014/05/28 00:00 [pmc-release]
AID - bjc2013187 [pii]
AID - 10.1038/bjc.2013.187 [doi]
PST - ppublish
SO  - Br J Cancer. 2013 May 28;108(10):2021-32. doi: 10.1038/bjc.2013.187. Epub 2013 
      Apr 30.