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"Double hit" makes the difference.
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MedLine Citation:
PMID:  22874594     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Authors:
Frédéric Bost
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Publication Detail:
Type:  Comment; News     Date:  2012-08-09
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-28     Completed Date:  2013-02-04     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2979     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Female
Glucose / metabolism*
Humans
Metformin / pharmacology*
Neoplastic Stem Cells / drug effects*
Chemical
Reg. No./Substance:
50-99-7/Glucose; 657-24-9/Metformin
Comments/Corrections
Comment On:
Cell Cycle. 2012 Aug 1;11(15):2782-92   [PMID:  22809961 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
ISSN: 1538-4101
ISSN: 1551-4005
Publisher: Landes Bioscience
Article Information
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Copyright © 2012 Landes Bioscience
open-access:
Print publication date: Day: 15 Month: 8 Year: 2012
pmc-release publication date: Day: 15 Month: 8 Year: 2012
Volume: 11 Issue: 16
First Page: 2979 Last Page: 2979
ID: 3442906
PubMed Id: 22874594
Publisher Id: 2012NV0743
DOI: 10.4161/cc.21532
Publisher Item Identifier: 21532

“Double hit” makes the difference
Frédéric Bost*
INSERM U1065; Centre Méditerranéen de Médecine Moléculaire; Team “Cellular and molecular physiophathology of obesity and diabetes;” Nice, France
*Correspondence to: Frédéric Bost, Email: bost@unice.fr

Metformin (N’, N’-dimethylbiguanide) is an anti-diabetic drug prescribed to more than 100 million patients in the world. In addition to its efficacy for the treatment of diabetes, several recent studies have shown that it has anti-tumoral properties.1 We and others have shown that metformin targets cancer cell metabolism by inhibiting mitochondrial complex 1 activity.2,3 This energetic stress leads to a decrease of intracellular ATP concentration, and cancer cells will increase their rate of glycolysis.2 This compensatory response is not sufficient to restore ATP levels, but is adequate to maintain viable cells in most of the cancer cells. Indeed, metformin blocks cell growth but can also induce apoptosis in some cancer cell models.4 The increase of glycolysis induced by metformin is somehow inconsistent with the observed inhibition of proliferation, since cancer cells use preferentially glycolysis to grow faster. This switch to glycolysis, also known as the “Warburg effect,” is linked to oncogenic transformation5 and is accompanied by the hyperactivation of the mTOR pathway. In cancer cells, the increase of glycolysis induced by metformin is associated with a strong inhibition of the mTOR pathway via the AMPK. This new metabolic order established by metformin may explain the paradoxical effect of metformin. In view of the above scenario, Menendez et al. decided to test the synthetic lethality of metformin and combined metformin treatment with glucose starvation. They showed that the treatment of breast cancer cells with metformin alone does not induce apoptosis but arrests cells in G0/G1. Glucose starvation by itself induces few apoptosis, but the combination of metformin with the absence of glucose induces massive apoptosis. This is not altogether surprising, since the dual action of metformin and glucose starvation block the two main ways of production of ATP (i.e., mitochondrial respiration and glycolysis) (Fig. 1). This is an interesting observation, which could be valuable for future anticancer therapy; however, glucose starvation is not therapeutically feasible. Thus, the use 2-deoxyglucose (2-DG), an inhibitor of glycolysis, could be useful. We and others found that the combination of 2-DG and metformin inhibits prostate cancer cell proliferation and breast tumor growth in xenograft models.2,6 Although it induces a slight apoptotic response in vitro, 2-DG alone is not efficient in vivo to alter tumor growth6 but improves the curative action of radiotherapy;7 similarly, it reinforces metformin action. Another interesting issue raised by Menendez et al. is the use of such dual therapy to target cancer stem cells. Metformin has been shown to selectively kill cancer stem cells and the chemotherapy-resistant subpopulation of cancer stem cells.8,9 Cancer stem cells greatly depend on aerobic glycolysis to sustain their stemness and immortality. The synthetic lethality induced by metformin and glucose starvation may help to improve chemotherapy action and avoid cancer relapse. In conclusion, targeting cancer cell metabolism with a “dual hit therapy” opens new avenues for the future treatment of cancer.


Notes

Previously published online: www.landesbioscience.com/journals/cc/article/21532

Notes


References
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Figures

[Figure ID: F1]

Figure 1. The combination of metformin and glucose starvation induces a strong energetic stress. Metformin inhibits the mitochondrial complex 1 and glucose starvation, or 2-DG inhibits ATP production from glycolysis. The combination of the two energetic stresses induces a massive energetic stress and leads to a strong apoptotic response.



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