Abstract:
Due to its severe cardiotoxicity, doxorubicin is typically administered as a
combination therapy in efforts to evoke a significant cytotoxic response while minimizing adverse cardiac effects. Protein kinase inhibitors have gained increasing popularity since the turn of the century as a result of their ability to target specific cancer pathways and reduce off-target effects. In this study, an shRNA whole-kinome screen was performed in
AC16 cardiomyocytes to identify the kinases associated with doxorubicin cardiotoxicity. Of the list of kinase inhibitors discovered to enhance doxorubicin cardiotoxicity in AC16 cells, Janus kinase inhibitors (JAK) were chosen to investigate their effects on doxorubicin-induced cardiotoxicity. The effects of JAKi on AC16 cardiomyocytes were first assessed, revealing that all tested JAKi elicited cardiotoxic effects at varying levels
of potency. Hence, a drug combination study was performed whereby AC16 cells were treated with doxorubicin and JAK inhibitors (JAKi) at various concentration ratios. Analysed by Combenefit and CalcuSyn, the combination of doxorubicin and JAKi evoked different degrees of toxicity synergism at selective combination concentrations. This entails that doxorubicin and JAKi combinations should be regarded with caution and
further research is required to determine its safety for future clinical application.
