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High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes
from Doxorubicin-Induced Damage
#MMPMID26137186
Gergely S
; Heged?s C
; Lakatos P
; Kovács K
; Gáspár R
; Csont T
; Virág L
Oxid Med Cell Longev
2015[]; 2015
(?): 178513
PMID26137186
show ga
Antracyclines are effective antitumor agents. One of the most commonly used
antracyclines is doxorubicin, which can be successfully used to treat a diverse
spectrum of tumors. Application of these drugs is limited by their cardiotoxic
effect, which is determined by a lifetime cumulative dose. We set out to identify
by high throughput screening cardioprotective compounds protecting cardiomyocytes
from doxorubicin-induced injury. Ten thousand compounds of ChemBridge's DIVERSet
compound library were screened to identify compounds that can protect H9C2 rat
cardiomyocytes against doxorubicin-induced cell death. The most effective
compound proved protective in doxorubicin-treated primary rat cardiomyocytes and
was further characterized to demonstrate that it significantly decreased
doxorubicin-induced apoptotic and necrotic cell death and inhibited
doxorubicin-induced activation of JNK MAP kinase without having considerable
radical scavenging effect or interfering with the antitumor effect of
doxorubicin. In fact the compound identified as
3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide
was toxic to all tumor cell lines tested even without doxorubicine treatment.
This benzimidazole compound may lead, through further optimalization, to the
development of a drug candidate protecting the heart from doxorubicin-induced
injury.
|Animals
[MESH]
|Antibiotics, Antineoplastic/*pharmacology
[MESH]
|Apoptosis/*drug effects
[MESH]
|Benzimidazoles/chemistry/*pharmacology
[MESH]
|Cell Proliferation/drug effects
[MESH]
|Cells, Cultured
[MESH]
|Doxorubicin/*pharmacology
[MESH]
|High-Throughput Screening Assays
[MESH]
|JNK Mitogen-Activated Protein Kinases/metabolism
[MESH]
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