A small molecule showing cardioprotection from drug-induced and alcohol-induced cytotoxicity.
Cardiotoxicity is one of the most common causes of drug withdrawal. Cardiotoxicity is a very much a concern during drug development as some drugs induce structural and/or electrophysiological alterations in heart muscle cells, significantly impeding drug development. Chemotherapy-induced cardiotoxicity is a major cause of early morbidity and mortality in children and adults with cancer during and after treatments. Many chemotherapeutic drugs, including carfilzomib, cause cardiotoxicity which manifests as a temporary or permanent reduction in left ventricular (LV) function inducing adverse cardiac events. Additionally, excessive alcohol use can lead to alcohol-induced cardiotoxicity which has traditionally been studied in animal-based models, but these models lack physiological relevance to humans and cannot be used for high-throughput screening of cardioprotective agents. There is an unmet need for therapeutics for cardioprotection in drug-induced and alcohol-induced cardiotoxicity.
Emory researchers have identified potential cardioprotective agents using human induced pluripotent stem cells (hiPSC-CMs) following screening of >2,000 small molecules. The technique uses human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) to reflect phycological conditions more accurately in humans when exposed to alcohol or toxic drugs. One of the small molecule candidates was shown to protect hiPSC-CMs from alcohol- and drug-induced cardiotoxicity and to mitigate carfilzomib-induced mitochondrial defects and prevent oxidative stress, without affecting the chemotherapy drug’s cancer killing ability. The inventors have now identified effective doses of the lead compound. Additional results and data show that the lead compound can protect hiPSC-CMs from doxorubicin- and bortezomib-induced cytotoxicity, indicating that the compound may have a broad impact for cardioprotection.
Inventors have identified effective doses of the lead compound.