Topoisomerase II inhibitors CX-5461 and Doxorubicin differ in their cardiotoxicity profiles

CX-5461 (CX) is a chemotherapeutic drug currently under investigation for the treatment of late-stage cancers. While CX was first described as an RNA polymerase I inhibitor, it has recently been shown to primarily inhibit the beta isoform of topoisomerase II. This isoform is also inhibited by anthracycline drugs including Doxorubicin (DOX) and mediates the toxic effects of these drugs on the heart. It is unclear whether CX will similarly cause cardiotoxicity. We therefore designed a study to test the effects of CX compared to DOX on iPSC-derived cardiomyocytes from six individuals. While both CX and DOX induce cell death in cardiomyocytes, CX is 20-fold less cytotoxic than DOX. At sub-lethal doses, DOX induces DNA damage, while CX does not. Transcriptome profiling following treatment with two sub-micromolar concentrations of both drugs over time reveals that DOX induces thousands of gene expression changes compared to hundreds induced by CX. Comparison of gene expression trajectories across drugs reveals that genes that respond to CX also respond to DOX, while most DOX response genes are drug specific. Shared response genes correspond to pathways related to chromosome segregation and DNA replication. CX does not affect the expression of any of the genes in functionally-validated loci associated with DOX-induced cardiotoxicity. Our data demonstrate that CX treatment of cardiomyocytes induces gene expression changes that mirror a subset of those induced by DOX; however these changes do not coincide with the cardiotoxicity observed with DOX treatment.