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

ABSTRACT: CX-5461 (CX) is a clinical-stage anticancer agent originally identified as an RNA polymerase I inhibitor, but more recently recognized for its ability to target the beta isoform of topoisomerase II (TOP2B). This isoform is also inhibited by anthracyclines such as Doxorubicin (DOX), a widely used chemotherapy drug known to cause cardiotoxicity. To investigate whether CX shares similar cardiotoxic potential, we compared its effects to DOX in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from six donors. Both drugs induced cell death, yet CX was markedly less cytotoxic than DOX, with an approximate 20-fold difference in potency. At sub-lethal concentrations, DOX led to significant DNA damage, whereas CX did not. Transcriptome analysis was performed across three timepoints following treatment with low and high sub-micromolar doses of each drug. Gene expression profiling revealed that DOX triggered extensive transcriptional reprogramming involving thousands of genes, while CX elicited a more restrained response affecting only hundreds. Time-course comparisons showed partial overlap in gene response trajectories, with CX-responsive genes representing a subset of the broader DOX-induced network. These shared genes were enriched for pathways involved in chromosome segregation and DNA replication. Importantly, analysis of genes located within functionally validated loci implicated in anthracycline-induced cardiotoxicity demonstrated that DOX altered the expression of ~80% of these genes, whereas CX had no measurable effect. These findings suggest that although CX can engage certain transcriptional programs similar to DOX, its overall impact on cardiomyocytes is substantially attenuated and does not resemble the cardiotoxic signature characteristic of DOX exposure.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302122 | GEO | 2025/12/11

REPOSITORIES: GEO

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Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

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

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