PMID- 23922888
OWN - NLM
STAT- MEDLINE
DCOM- 20140325
LR  - 20220318
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 7
DP  - 2013
TI  - Metformin, a diabetes drug, eliminates tumor-initiating hepatocellular carcinoma 
      cells.
PG  - e70010
LID - 10.1371/journal.pone.0070010 [doi]
LID - e70010
AB  - Metformin has been widely used as an oral drug for diabetes mellitus for 
      approximately 60 years. Interestingly, recent reports showed that metformin 
      exhibited an anti-tumor action in a wide range of malignancies including 
      hepatocellular carcinoma (HCC). In the present study, we investigated its impact 
      on tumor-initiating HCC cells. Metformin suppressed cell growth and induced 
      apoptosis in a dose-dependent manner. Flow cytometric analysis showed that 
      metformin treatment markedly reduced the number of tumor-initiating epithelial 
      cell adhesion molecule (EpCAM)(+) HCC cells. Non-adherent sphere formation assays 
      of EpCAM(+) cells showed that metformin impaired not only their sphere-forming 
      ability, but also their self-renewal capability. Consistent with this, 
      immunostaining of spheres revealed that metformin significantly decreased the 
      number of component cells positive for hepatic stem cell markers such as EpCAM 
      and alpha-fetoprotein. In a xenograft transplantation model using non-obese 
      diabetic/severe combined immunodeficient mice, metformin and/or sorafenib 
      treatment suppressed the growth of tumors derived from transplanted HCC cells. 
      Notably, the administration of metformin but not sorafenib decreased the number 
      of EpCAM(+) cells and impaired their self-renewal capability. As reported, 
      metformin activated AMP-activated protein kinase (AMPK) through phosphorylation; 
      however its inhibitory effect on the mammalian target of rapamycin (mTOR) pathway 
      did not necessarily correlate with its anti-tumor activity toward EpCAM(+) 
      tumor-initiating HCC cells. These results indicate that metformin is a promising 
      therapeutic agent for the elimination of tumor-initiating HCC cells and suggest 
      as-yet-unknown functions other than its inhibitory effect on the AMPK/mTOR 
      pathway.
FAU - Saito, Tomoko
AU  - Saito T
AD  - Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba 
      University, Chiba, Japan.
FAU - Chiba, Tetsuhiro
AU  - Chiba T
FAU - Yuki, Kaori
AU  - Yuki K
FAU - Zen, Yoh
AU  - Zen Y
FAU - Oshima, Motohiko
AU  - Oshima M
FAU - Koide, Shuhei
AU  - Koide S
FAU - Motoyama, Tenyu
AU  - Motoyama T
FAU - Ogasawara, Sadahisa
AU  - Ogasawara S
FAU - Suzuki, Eiichiro
AU  - Suzuki E
FAU - Ooka, Yoshihiko
AU  - Ooka Y
FAU - Tawada, Akinobu
AU  - Tawada A
FAU - Tada, Motohisa
AU  - Tada M
FAU - Kanai, Fumihiko
AU  - Kanai F
FAU - Takiguchi, Yuichi
AU  - Takiguchi Y
FAU - Iwama, Atsushi
AU  - Iwama A
FAU - Yokosuka, Osamu
AU  - Yokosuka O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130729
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hypoglycemic Agents)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Carcinoma, Hepatocellular/*drug therapy
MH  - Cell Cycle/drug effects
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Flow Cytometry
MH  - Hepatocytes/drug effects
MH  - Humans
MH  - Hypoglycemic Agents/*therapeutic use
MH  - Liver Neoplasms/*drug therapy
MH  - Metformin/*therapeutic use
MH  - Mice
MH  - Xenograft Model Antitumor Assays
PMC - PMC3726625
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/08 06:00
MHDA- 2014/03/26 06:00
PMCR- 2013/07/29
CRDT- 2013/08/08 06:00
PHST- 2013/04/08 00:00 [received]
PHST- 2013/06/13 00:00 [accepted]
PHST- 2013/08/08 06:00 [entrez]
PHST- 2013/08/08 06:00 [pubmed]
PHST- 2014/03/26 06:00 [medline]
PHST- 2013/07/29 00:00 [pmc-release]
AID - PONE-D-13-14452 [pii]
AID - 10.1371/journal.pone.0070010 [doi]
PST - epublish
SO  - PLoS One. 2013 Jul 29;8(7):e70010. doi: 10.1371/journal.pone.0070010. Print 2013.