PMID- 21521688
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 25
DP  - 2011 Jun 24
TI  - Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced 
      cardiomyocyte death by multiple mechanisms.
PG  - 21993-2006
LID - 10.1074/jbc.M111.225805 [doi]
AB  - Caloric restriction (CR) is a dietary intervention known to enhance 
      cardiovascular health. The glucose analog 2-deoxy-D-glucose (2-DG) mimics CR 
      effects in several animal models. However, whether 2-DG is beneficial to the 
      heart remains obscure. Here, we tested the ability of 2-DG to reduce 
      cardiomyocyte death triggered by doxorubicin (DOX, 1 mum), an antitumor drug that 
      can cause heart failure. Treatment of neonatal rat cardiomyocytes with 0.5 mm 
      2-DG dramatically suppressed DOX cytotoxicity as indicated by a decreased number 
      of cells that stained positive for propidium iodide and reduced apoptotic 
      markers. 2-DG decreased intracellular ATP levels by 17.9%, but it prevented 
      DOX-induced severe depletion of ATP, which may contribute to 2-DG-mediated 
      cytoprotection. Also, 2-DG increased the activity of AMP-activated protein kinase 
      (AMPK). Blocking AMPK signaling with compound C or small interfering RNA-mediated 
      knockdown of the catalytic subunit markedly attenuated the protective effects of 
      2-DG. Conversely, AMPK activation by pharmacological or genetic approach reduced 
      DOX cardiotoxicity but did not produce additive effects when used together with 
      2-DG. In addition, 2-DG induced autophagy, a cellular degradation pathway whose 
      activation could be either protective or detrimental depending on the context. 
      Paradoxically, despite its ability to activate autophagy, 2-DG prevented 
      DOX-induced detrimental autophagy. Together, these results suggest that the CR 
      mimetic 2-DG can antagonize DOX-induced cardiomyocyte death, which is mediated 
      through multiple mechanisms, including the preservation of ATP content, the 
      activation of AMPK, and the inhibition of autophagy.
FAU - Chen, Kai
AU  - Chen K
AD  - Cardiovascular Health Research Center, Sanford Research/University of South 
      Dakota, Sioux Falls, South Dakota 57104, USA.
FAU - Xu, Xianmin
AU  - Xu X
FAU - Kobayashi, Satoru
AU  - Kobayashi S
FAU - Timm, Derek
AU  - Timm D
FAU - Jepperson, Tyler
AU  - Jepperson T
FAU - Liang, Qiangrong
AU  - Liang Q
LA  - eng
GR  - P20 RR017662/RR/NCRR NIH HHS/United States
GR  - 2P20RR017662-06A1/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110426
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 80168379AG (Doxorubicin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Autophagy/drug effects
MH  - *Caloric Restriction
MH  - Cell Death/*drug effects
MH  - Cytoprotection/drug effects
MH  - Deoxyglucose/*pharmacology
MH  - Doxorubicin/*adverse effects/*antagonists & inhibitors
MH  - Myocytes, Cardiac/*cytology/*drug effects/enzymology/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC3121344
EDAT- 2011/04/28 06:00
MHDA- 2011/08/31 06:00
PMCR- 2012/06/24
CRDT- 2011/04/28 06:00
PHST- 2011/04/28 06:00 [entrez]
PHST- 2011/04/28 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
PHST- 2012/06/24 00:00 [pmc-release]
AID - S0021-9258(19)48907-2 [pii]
AID - M111.225805 [pii]
AID - 10.1074/jbc.M111.225805 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Jun 24;286(25):21993-2006. doi: 10.1074/jbc.M111.225805. Epub 
      2011 Apr 26.