Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27679486
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That
Target Chemoresistant Glioma Cells
#MMPMID27679486
Oliva CR
; Markert T
; Ross LJ
; White EL
; Rasmussen L
; Zhang W
; Everts M
; Moellering DR
; Bailey SM
; Suto MJ
; Griguer CE
J Biol Chem
2016[Nov]; 291
(46
): 24188-24199
PMID27679486
show ga
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.
|*Glioma/drug therapy/enzymology
[MESH]
|Animals
[MESH]
|Cell Line, Tumor
[MESH]
|Cytochromes c/metabolism
[MESH]
|Drug Resistance, Neoplasm/*drug effects
[MESH]
|Electron Transport Complex IV/*antagonists & inhibitors/metabolism
[MESH]
free
free
free
