PMID- 29861847
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240318
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 9
IP  - 38
DP  - 2018 May 18
TI  - Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic 
      lymphocytic leukemia cells.
PG  - 24980-24991
LID - 10.18632/oncotarget.25166 [doi]
AB  - Blood cells from patients with chronic lymphocytic leukemia (CLL) are 
      replicationally quiescent but transcriptionally, translationally, and 
      metabolically active. Recently, we demonstrated that oxidative phosphorylation 
      (OxPhos) is a predominant pathway in CLL for energy production and is further 
      augmented in the presence of the stromal microenvironment. Importantly, CLL cells 
      from patients with poor prognostic markers showed increased OxPhos. From these 
      data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, 
      currently in clinical development, is a small-molecule, orally bioavailable 
      OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL 
      cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death 
      at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos 
      and diminished intracellular ribonucleotide pools. However, glycolysis and 
      glucose uptake were induced as compensatory mechanisms. To mitigate the 
      upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with 
      IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell 
      death. Consistent with these data, low-glucose culture conditions sensitized CLL 
      cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to 
      use a different metabolic pathway when OxPhos is inhibited and that targeting 
      both OxPhos and glycolysis pathways is necessary for biological effect.
FAU - Vangapandu, Hima V
AU  - Vangapandu HV
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Alston, Brandon
AU  - Alston B
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Morse, Joshua
AU  - Morse J
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Ayres, Mary L
AU  - Ayres ML
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
FAU - Wierda, William G
AU  - Wierda WG
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Keating, Michael J
AU  - Keating MJ
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - Institute of Applied Cancer Science and the Center for Co-Clinical Trials, The 
      University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
FAU - Gandhi, Varsha
AU  - Gandhi V
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, Texas, USA.
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, Texas, USA.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20180518
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
PMC - PMC5982765
OTO - NOTNLM
OT  - 2-dG
OT  - IACS-010759
OT  - OxPhos
OT  - metabolism
OT  - mitochondria
COIS- CONFLICTS OF INTEREST The authors have no financial or other conflicts of 
      interests.
EDAT- 2018/06/05 06:00
MHDA- 2018/06/05 06:01
PMCR- 2018/05/18
CRDT- 2018/06/05 06:00
PHST- 2017/08/14 00:00 [received]
PHST- 2018/01/09 00:00 [accepted]
PHST- 2018/06/05 06:00 [entrez]
PHST- 2018/06/05 06:00 [pubmed]
PHST- 2018/06/05 06:01 [medline]
PHST- 2018/05/18 00:00 [pmc-release]
AID - 25166 [pii]
AID - 10.18632/oncotarget.25166 [doi]
PST - epublish
SO  - Oncotarget. 2018 May 18;9(38):24980-24991. doi: 10.18632/oncotarget.25166. 
      eCollection 2018 May 18.