|"Double hit" makes the difference.|
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|PMID: 22874594 Owner: NLM Status: MEDLINE|
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|Type: Comment; News Date: 2012-08-09|
|Title: Cell cycle (Georgetown, Tex.) Volume: 11 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2012 Aug|
|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|
|Languages: eng Pagination: 2979 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Apoptosis / drug effects*
Glucose / metabolism*
Metformin / pharmacology*
Neoplastic Stem Cells / drug effects*
|Cell Cycle. 2012 Aug 1;11(15):2782-92
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
Publisher: Landes Bioscience
Copyright © 2012 Landes Bioscience
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
PubMed Id: 22874594
Publisher Id: 2012NV0743
Publisher Item Identifier: 21532
|“Double hit” makes the difference|
|INSERM U1065; Centre Méditerranéen de Médecine Moléculaire; Team “Cellular and molecular physiophathology of obesity and diabetes;” Nice, France
|*Correspondence to: Frédéric Bost, Email: email@example.com
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.
Previously published online: www.landesbioscience.com/journals/cc/article/21532
|1.||Ben Sahra I,et al. Mol Cancer TherYear: 201091092910.1158/1535-7163.MCT-09-118620442309|
|2.||Ben Sahra I,et al. Cancer ResYear: 20107024657510.1158/0008-5472.CAN-09-278220215500|
|3.||Buzzai M,et al. Cancer ResYear: 20076767455210.1158/0008-5472.CAN-06-444717638885|
|4.||Tomic T,et al. Cell Death DisYear: 20112e19910.1038/cddis.2011.8621881601|
|5.||Kroemer G,Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heelCancer CellYear: 2008134728210.1016/j.ccr.2008.05.00518538731|
|6.||Cheong JH,et al. Mol Cancer TherYear: 20111023506210.1158/1535-7163.MCT-11-049721992792|
|7.||Mohanti BK,et al. Int J Radiat Oncol Biol PhysYear: 1996351031110.1016/S0360-3016(96)85017-68641905|
|8.||Hirsch HA,et al. Cancer ResYear: 20096975071110.1158/0008-5472.CAN-09-299419752085|
|9.||Iliopoulos D,et al. Cancer ResYear: 201171319620110.1158/0008-5472.CAN-10-347121415163|
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