PMID- 27679486
OWN - NLM
STAT- MEDLINE
DCOM- 20170524
LR  - 20230131
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 291
IP  - 46
DP  - 2016 Nov 11
TI  - Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That 
      Target Chemoresistant Glioma Cells.
PG  - 24188-24199
AB  - The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.1) is a large 
      transmembrane protein complex that serves as the last enzyme in the respiratory 
      electron transport chain of eukaryotic mitochondria. CcO promotes the switch from 
      glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been 
      associated with increased self-renewal characteristics in gliomas. Increased CcO 
      activity in tumors has been associated with tumor progression after chemotherapy 
      failure, and patients with primary glioblastoma multiforme and high tumor CcO 
      activity have worse clinical outcomes than those with low tumor CcO activity. 
      Therefore, CcO is an attractive target for cancer therapy. We report here the 
      characterization of a CcO inhibitor (ADDA 5) that was identified using a high 
      throughput screening paradigm. ADDA 5 demonstrated specificity for CcO, with no 
      inhibition of other mitochondrial complexes or other relevant enzymes, and 
      biochemical characterization showed that this compound is a non-competitive 
      inhibitor of cytochrome c When tested in cellular assays, ADDA 5 dose-dependently 
      inhibited the proliferation of chemosensitive and chemoresistant glioma cells but 
      did not display toxicity against non-cancer cells. Furthermore, treatment with 
      ADDA 5 led to significant inhibition of tumor growth in flank xenograft mouse 
      models. Importantly, ADDA 5 inhibited CcO activity and blocked cell proliferation 
      and neurosphere formation in cultures of glioma stem cells, the cells implicated 
      in tumor recurrence and resistance to therapy in patients with glioblastoma. In 
      summary, we have identified ADDA 5 as a lead CcO inhibitor for further 
      optimization as a novel approach for the treatment of glioblastoma and related 
      cancers.
CI  - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Oliva, Claudia R
AU  - Oliva CR
AD  - From the Department of Neurosurgery.
FAU - Markert, Tahireh
AU  - Markert T
AD  - From the Department of Neurosurgery.
FAU - Ross, Larry J
AU  - Ross LJ
AD  - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205.
FAU - White, E Lucile
AU  - White EL
AD  - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205.
FAU - Rasmussen, Lynn
AU  - Rasmussen L
AD  - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205.
FAU - Everts, Maaike
AU  - Everts M
AD  - Department of Pediatrics, Division of Infectious Diseases, University of Alabama 
      at Birmingham, Birmingham, Alabama 35294.
FAU - Moellering, Douglas R
AU  - Moellering DR
AD  - UAB Nutrition Sciences Department, Diabetes Research Center BARB Core, University 
      of Alabama at Birmingham, Birmingham, Alabama 35294.
FAU - Bailey, Shannon M
AU  - Bailey SM
AD  - Department of Pathology, Division of Molecular and Cellular Pathology, University 
      of Alabama at Birmingham, Birmingham, Alabama 35294, and.
FAU - Suto, Mark J
AU  - Suto MJ
AD  - Drug Discovery Division, Southern Research, Birmingham, Alabama 35205.
FAU - Griguer, Corinne E
AU  - Griguer CE
AD  - From the Department of Neurosurgery, cegriguer@uabmc.edu.
AD  - Center for Free Radical Biology, and.
LA  - eng
GR  - P30 DK079626/DK/NIDDK NIH HHS/United States
GR  - R01 CA160821/CA/NCI NIH HHS/United States
GR  - UL1 TR000165/TR/NCATS NIH HHS/United States
GR  - UL1 TR001417/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20160927
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Neoplasm Proteins)
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cytochromes c/metabolism
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Electron Transport Complex IV/*antagonists & inhibitors/metabolism
MH  - Enzyme Inhibitors/*pharmacology
MH  - *Glioma/drug therapy/enzymology
MH  - Humans
MH  - Mice
MH  - Neoplasm Proteins/*antagonists & inhibitors/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC5104942
OTO - NOTNLM
OT  - chemoresistance
OT  - cytochrome c oxidase (complex IV)
OT  - glioblastoma
OT  - inhibitor
OT  - metabolism
OT  - mitochondria
OT  - small molecule
OT  - stem cells
EDAT- 2016/09/30 06:00
MHDA- 2017/05/26 06:00
PMCR- 2017/11/11
CRDT- 2016/09/29 06:00
PHST- 2016/07/22 00:00 [received]
PHST- 2016/09/25 00:00 [revised]
PHST- 2016/09/30 06:00 [pubmed]
PHST- 2017/05/26 06:00 [medline]
PHST- 2016/09/29 06:00 [entrez]
PHST- 2017/11/11 00:00 [pmc-release]
AID - S0021-9258(20)34686-X [pii]
AID - M116.749978 [pii]
AID - 10.1074/jbc.M116.749978 [doi]
PST - ppublish
SO  - J Biol Chem. 2016 Nov 11;291(46):24188-24199. doi: 10.1074/jbc.M116.749978. Epub 
      2016 Sep 27.