High throughput screening identifies a novel compound protecting cardiomyocytes from doxorubicin-induced damage

Antracyclines are effective anti-tumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors, including breast -, lung -, thyroid gland tumors and leukemias. Application of these drugs is limited mainly by their cardiotoxic effect, which is determined by a lifetime cumulative dose. As the processes that are responsible for tumor chemotherapy and cardiotoxicity are different, this may give a hope for eliminating the side effect without affecting the anti-tumor effect. In our recent work, 10 000 compounds of the Chembridge's Diverset compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. An MTT-based high throughput viability screening was performed followed by retesting of the hit compounds in a morphology-based assay. The most effective compound proved protective in DOX-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death, inhibited DOX-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of DOX. 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 DOXinduced injury.