PMID- 20810672
OWN - NLM
STAT- MEDLINE
DCOM- 20101214
LR  - 20231213
IS  - 1940-6215 (Electronic)
IS  - 1940-6207 (Print)
IS  - 1940-6215 (Linking)
VI  - 3
IP  - 9
DP  - 2010 Sep
TI  - Metformin prevents tobacco carcinogen--induced lung tumorigenesis.
PG  - 1066-76
LID - 10.1158/1940-6207.CAPR-10-0055 [doi]
AB  - Activation of the mammalian target of rapamycin (mTOR) pathway is an important 
      and early event in tobacco carcinogen-induced lung tumorigenesis, and therapies 
      that target mTOR could be effective in the prevention or treatment of lung 
      cancer. The biguanide metformin, which is widely prescribed for the treatment of 
      type II diabetes, might be a good candidate for lung cancer chemoprevention 
      because it activates AMP-activated protein kinase (AMPK), which can inhibit the 
      mTOR pathway. To test this, A/J mice were treated with oral metformin after 
      exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
      (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state plasma 
      concentrations that are achievable in humans. mTOR was inhibited in lung tumors 
      but only modestly. To test whether intraperitoneal administration of metformin 
      might improve mTOR inhibition, we injected mice and assessed biomarkers in liver 
      and lung tissues. Plasma levels of metformin were significantly higher after 
      injection than oral administration. In liver tissue, metformin activated AMPK and 
      inhibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited 
      phosphorylation of insulin-like growth factor-I receptor/insulin receptor 
      (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. This 
      suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing 
      activation of insulin-like growth factor-I receptor/insulin receptor and Akt 
      upstream of mTOR. Based on these data, we repeated the NNK-induced lung 
      tumorigenesis study using intraperitoneal administration of metformin. Metformin 
      decreased tumor burden by 72%, which correlated with decreased cellular 
      proliferation and marked inhibition of mTOR in tumors. These studies show that 
      metformin prevents tobacco carcinogen-induced lung tumorigenesis and support 
      clinical testing of metformin as a chemopreventive agent.
FAU - Memmott, Regan M
AU  - Memmott RM
AD  - National Cancer Institute/Navy Medical Oncology, Room 5101, Building 8, 8901 
      Wisconsin Avenue, Bethesda, MD 20889, USA.
FAU - Mercado, Jose R
AU  - Mercado JR
FAU - Maier, Colleen R
AU  - Maier CR
FAU - Kawabata, Shigeru
AU  - Kawabata S
FAU - Fox, Stephen D
AU  - Fox SD
FAU - Dennis, Phillip A
AU  - Dennis PA
LA  - eng
PT  - Journal Article
DEP - 20100901
PL  - United States
TA  - Cancer Prev Res (Phila)
JT  - Cancer prevention research (Philadelphia, Pa.)
JID - 101479409
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carcinogens)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Nitrosamines)
RN  - 7S395EDO61 (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.4.3 (Adenylate Kinase)
SB  - IM
CIN - Cancer Prev Res (Phila). 2010 Sep;3(9):1049-52. PMID: 20810671
MH  - Adenylate Kinase/metabolism
MH  - Administration, Oral
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/blood/pharmacology/therapeutic use
MH  - *Carcinogens
MH  - Carcinoma/chemically induced/*prevention & control
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - Hypoglycemic Agents/administration & dosage/pharmacology/therapeutic use
MH  - Injections, Intraperitoneal
MH  - Lung Neoplasms/chemically induced/*prevention & control
MH  - Metformin/administration & dosage/blood/pharmacology/*therapeutic use
MH  - Mice
MH  - Nitrosamines
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Nicotiana/*adverse effects/chemistry
PMC - PMC3192328
MID - NIHMS209213
EDAT- 2010/09/03 06:00
MHDA- 2010/12/16 06:00
PMCR- 2011/10/13
CRDT- 2010/09/03 06:00
PHST- 2010/09/03 06:00 [entrez]
PHST- 2010/09/03 06:00 [pubmed]
PHST- 2010/12/16 06:00 [medline]
PHST- 2011/10/13 00:00 [pmc-release]
AID - 1940-6207.CAPR-10-0055 [pii]
AID - 10.1158/1940-6207.CAPR-10-0055 [doi]
PST - ppublish
SO  - Cancer Prev Res (Phila). 2010 Sep;3(9):1066-76. doi: 
      10.1158/1940-6207.CAPR-10-0055. Epub 2010 Sep 1.