Novel Mechanism of and Therapeutic Approach for Anthracycline-Induced Cardiotoxicity.

UNLABELLED: Anthracyclines are potent chemotherapeutic agents known for their efficacy in treating various cancers via inhibition of topoisomerase II α (TOP2A). However, their clinical use is limited due to cardiotoxicity, primarily attributed to off-target inhibition of topoisomerase II β (TOP2B) in cardiomyocytes. The well-accepted mechanism involves TOP2B inhibition as a key driver of this toxicity. In this study, we identify a novel mechanism of anthracycline-induced cardiotoxicity (AIC) involving upregulated TOP2B expression and its direct impact on cardiomyocyte function. Our data show that doxorubicin significantly increased TOP2B protein levels in cardiomyocytes in AIC mouse models. The cardiomyocyte-specific, tamoxifen-inducible TOP2B transgenic mice exhibited pathophysiologic features consistent with doxorubicin-induced cardiotoxicity, even without exposure to anthracyclines. Additionally, we discovered that TOP2B binds to SMYD1, a histone methyltransferase critical for muscle cell function. Mutations in SMYD1 are known to cause cardiomyopathy and heart failure in humans, and loss of Smyd1 in mice results in a phenotype resembling AIC. More importantly, TOP2B antisense oligonucleotide (ASO) pretreatment can succussfully prevent AIC in TOP2B transgenic mice and AIC mouse models. Our findings reveal a novel role for TOP2B in AIC, demonstrating that its upregulation disrupts SMYD1 function in cardiomyocytes, contributing to cardiotoxicity. This study also highlights the therapeutic potential of targeting TOP2B using ASO for preventing AIC in patients with cancer, offering new insights into cardioprotective strategies.

SIGNIFICANCE: Anthracycline chemotherapy can cause severe and sometimes fatal heart damage, limiting its clinical use. We identify TOP2B upregulation as a key driver of cardiotoxicity and demonstrate that ASO therapy targeting TOP2B prevents heart failure and improves survival in preclinical models, providing a promising strategy to protect patients with cancer during chemotherapy.