High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage

Abstract EN

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.