PMID- 24456076
OWN - NLM
STAT- MEDLINE
DCOM- 20140508
LR  - 20140317
IS  - 1365-2141 (Electronic)
IS  - 0007-1048 (Linking)
VI  - 165
IP  - 1
DP  - 2014 Apr
TI  - Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute 
      lymphoblastic leukaemia.
PG  - 57-66
LID - 10.1111/bjh.12727 [doi]
AB  - Drug-resistant forms of acute lymphoblastic leukaemia (ALL) are a leading cause 
      of death from disease in children. Up to 25% of patients with T-cell ALL (T-ALL) 
      develop resistance to chemotherapeutic agents, particularly to glucocorticoids 
      (GCs), a class of drug to which resistance is one of the strongest indicators of 
      poor clinical outcome. Despite their clinical importance, the molecular 
      mechanisms that underpin GC resistance and leukaemia relapse are not well 
      understood. Recently, we demonstrated that GC-resistance is associated with a 
      proliferative metabolism involving the up-regulation of glycolysis, oxidative 
      phosphorylation and cholesterol biosynthesis. Here we confirm that resistance is 
      directly associated with a glycolytic phenotype and show that GC-resistant T-ALL 
      cells are able to shift between glucose bioenergetic pathways. We evaluated the 
      potential for targeting these pathways in vitro using a glycolysis inhibitor, 
      2-deoxyglucose (2DG), and the oxidative phosphorylation inhibitor oligomycin in 
      combination with methylprednisolone (MPRED). We found that oligomycin synergized 
      with MPRED to sensitize cells otherwise resistant to GCs. Similarly we observed 
      synergy between MPRED and simvastatin, an inhibitor of cholesterol metabolism. 
      Collectively, our findings suggest that dual targeting of bioenergetic pathways 
      in combination with GCs may offer a promising therapeutic strategy to overcome 
      drug resistance in ALL.
CI  - (c) 2014 John Wiley & Sons Ltd.
FAU - Samuels, Amy L
AU  - Samuels AL
AD  - Division of Children's Leukaemia and Cancer Research, Telethon Institute for 
      Child Health Research, Centre for Child Health Research, University of Western 
      Australia, Perth, WA, Australia.
FAU - Heng, Jasmin Y
AU  - Heng JY
FAU - Beesley, Alex H
AU  - Beesley AH
FAU - Kees, Ursula R
AU  - Kees UR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140123
PL  - England
TA  - Br J Haematol
JT  - British journal of haematology
JID - 0372544
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Glucocorticoids)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Oligomycins)
RN  - X2RN3Q8DNE (Galactose)
RN  - X4W7ZR7023 (Methylprednisolone)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - *Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - Galactose/metabolism
MH  - Glucocorticoids/pharmacology/therapeutic use
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
MH  - Methylprednisolone/pharmacology/therapeutic use
MH  - Mitochondria/drug effects/metabolism
MH  - Oligomycins/pharmacology
MH  - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*metabolism
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - acute lymphoblastic leukaemia
OT  - glucocorticoid
OT  - glycolysis
OT  - metabolism
OT  - resistance
EDAT- 2014/01/25 06:00
MHDA- 2014/05/09 06:00
CRDT- 2014/01/25 06:00
PHST- 2013/09/23 00:00 [received]
PHST- 2013/12/05 00:00 [accepted]
PHST- 2014/01/25 06:00 [entrez]
PHST- 2014/01/25 06:00 [pubmed]
PHST- 2014/05/09 06:00 [medline]
AID - 10.1111/bjh.12727 [doi]
PST - ppublish
SO  - Br J Haematol. 2014 Apr;165(1):57-66. doi: 10.1111/bjh.12727. Epub 2014 Jan 23.