PMID- 21931801
OWN - NLM
STAT- MEDLINE
DCOM- 20120228
LR  - 20220330
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 9
DP  - 2011
TI  - Acquisition of chemoresistance in gliomas is associated with increased 
      mitochondrial coupling and decreased ROS production.
PG  - e24665
LID - 10.1371/journal.pone.0024665 [doi]
LID - e24665
AB  - Temozolomide (TMZ) is an alkylating agent used for treating gliomas. 
      Chemoresistance is a severe limitation to TMZ therapy; there is a critical need 
      to understand the underlying mechanisms that determine tumor response to TMZ. We 
      recently reported that chemoresistance to TMZ is related to a remodeling of the 
      entire electron transport chain, with significant increases in the activity of 
      complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and 
      genetic manipulation of CcO reverses chemoresistance. Therefore, to test the 
      hypothesis that TMZ-resistance arises from tighter mitochondrial coupling and 
      decreased production of reactive oxygen species (ROS), we have assessed 
      mitochondrial function in TMZ-sensitive and -resistant glioma cells, and in 
      TMZ-resistant glioblastoma multiform (GBM) xenograft lines (xenolines). Maximum 
      ADP-stimulated (state 3) rates of mitochondrial oxygen consumption were greater 
      in TMZ-resistant cells and xenolines, and basal respiration (state 2), proton 
      leak (state 4), and mitochondrial ROS production were significantly lower in 
      TMZ-resistant cells. Furthermore, TMZ-resistant cells consumed less glucose and 
      produced less lactic acid. Chemoresistant cells were insensitive to the oxidative 
      stress induced by TMZ and hydrogen peroxide challenges, but treatment with the 
      oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and 
      reversed chemoresistance. Importantly, treatment with the antioxidant 
      N-acetyl-cysteine inhibited TMZ-dependent ROS generation in chemosensitive cells, 
      preventing TMZ toxicity. Finally, we found that mitochondrial DNA-depleted cells 
      (rho degrees ) were resistant to TMZ and had lower intracellular ROS levels after TMZ 
      exposure compared with parental cells. Repopulation of rho degrees  cells with mitochondria 
      restored ROS production and sensitivity to TMZ. Taken together, our results 
      indicate that chemoresistance to TMZ is linked to tighter mitochondrial coupling 
      and low ROS production, and suggest a novel mitochondrial ROS-dependent mechanism 
      underlying TMZ-chemoresistance in glioma. Thus, perturbation of mitochondrial 
      functions and changes in redox status might constitute a novel strategy for 
      sensitizing glioma cells to therapeutic approaches.
FAU - Oliva, Claudia R
AU  - Oliva CR
AD  - Division of Neurosurgery, Department of Surgery, University of Alabama at 
      Birmingham, Birmingham, Alabama, United States of America.
FAU - Moellering, Douglas R
AU  - Moellering DR
FAU - Gillespie, G Yancey
AU  - Gillespie GY
FAU - Griguer, Corinne E
AU  - Griguer CE
LA  - eng
GR  - R01 CA160821/CA/NCI NIH HHS/United States
GR  - R21 CA139290/CA/NCI NIH HHS/United States
GR  - P60 DK079626/DK/NIDDK NIH HHS/United States
GR  - P20 CA151129/CA/NCI NIH HHS/United States
GR  - P30 CA13148-35/CA/NCI NIH HHS/United States
GR  - P30 CA013148/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110909
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Reactive Oxygen Species)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - GAN16C9B8O (Glutathione)
RN  - ULW86O013H (Glutathione Disulfide)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Antineoplastic Agents, Alkylating/pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - DNA, Mitochondrial/metabolism
MH  - Dacarbazine/analogs & derivatives/pharmacology
MH  - Drug Resistance, Neoplasm
MH  - Electron Transport Complex IV/metabolism
MH  - Glioma/*metabolism
MH  - Glutathione/metabolism
MH  - Glutathione Disulfide/metabolism
MH  - Humans
MH  - Reactive Oxygen Species/*metabolism
MH  - Temozolomide
PMC - PMC3170372
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/09/21 06:00
MHDA- 2012/03/01 06:00
PMCR- 2011/09/09
CRDT- 2011/09/21 06:00
PHST- 2011/07/25 00:00 [received]
PHST- 2011/08/15 00:00 [accepted]
PHST- 2011/09/21 06:00 [entrez]
PHST- 2011/09/21 06:00 [pubmed]
PHST- 2012/03/01 06:00 [medline]
PHST- 2011/09/09 00:00 [pmc-release]
AID - PONE-D-11-14137 [pii]
AID - 10.1371/journal.pone.0024665 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(9):e24665. doi: 10.1371/journal.pone.0024665. Epub 2011 Sep 9.