Introduction: Cardiotoxicity is now recognized as one of the leading causes of long-term morbidity and mortality in cancer survivors. With exponentially increasing number of targeted anti-cancer drugs come many, frequently unexpected, on- and off-target effects that can contribute to the wide variability in cardiovascular (CV) effects and toxicities. To date, overlapping cardiotoxicity mechanism(s) have not been extensively investigated for different anti-cancer agents.
Objective: We aimed to elucidate shared gene changes associated with cardiotoxicities induced by 2 different classes of chemotherapies: anthracyclines (Doxorubicin (DOX)) and proteasomal inhibitors (Carfilzomib (CFZ)). We also examined whether DNA methylation of these genes are involved in the cardiotoxic mechanism(s) of these anti-cancer agents.
Methods and results: Primary Human cardiomyocytes (HCMs) were treated with 1µM of DOX and CFZ for 72 hours. Both DOX and CFZ induced significantly reduced HCM cell viability as measured by Cell Titre Glo, by approximately 50% (EC50). Cells were collected for RNA-seq as well as for DNA methylation analysis using the MethylationEPIC bead chip array. DNA methylation analysis revealed 0 differentially methylated probes for DOX vs VEH and only 1 in the promotor region of the GLIPR2 gene for CZ vs VEH group (FDR <0.05). On the other hand, RNA-seq revealed 11,011 and 10,618 for the DOX and CZ treatments respectfully (FDR<0.05). We identified 5,643 differentially expressed genes (DEGs) that were commonly upregulated or downregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signaling pathway was the most significantly enriched pathway with common DEGs, shared between DOX and CFZ.
Conclusion: We identified that PI3K-Akt signaling pathway may be a potential shared mechanism(s) for CFZ or DOX-mediated cardiotoxicity. DNA methylation may not be involved in CFZ or DOX-mediated cardiotoxicity.