Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice

Abstract

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients ( n = 30) and replicated key findings in a second cohort ( n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx −/− mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

“…To evaluate the involvement of Cyp1 enzymes in Dox-induced cardiomyopathy, we first examined the expression of Cyp1a1 , Cyp1a2 , and Cyp1b1 by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in the liver and myocardium of mice treated with saline or Dox, using a low-dose Dox regimen that phenocopies the chronic toxicity observed in human patients. 39,41 To assess the expression of Cyp1 shortly after administering Dox, mice were sacrificed within 24 hours of the last dose of Dox, and hearts and livers were collected. All Cyp1 genes were expressed in both tissues.…”

Use of Deep‐Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin‐Induced Cardiotoxicity

“…[ 11 ] Moreover, a recent study by Liu et al in anthracycline‐treated breast cancer patients identified hemopexin as a biomarker associated with DIC, which is a circulating glycoprotein that binds to heme and facilitates its recycling in the reticuloendothelial system. [ 49 ] Hemopexin mitigates Dox‐induced ferroptosis and delivered cardiac protective function in Dox‐treated mice model. Nevertheless, increased TUNEL staining was also detected in our H9C2 model upon Dox treatment, as well as AIF's nuclear translocation, suggesting the involvement of apoptotic pathway, both caspase‐dependent and ‐independent, in Dox‐induced cardiotoxicity.…”

“…Temperature-Dependent Thermal Shift Assay: H9C2 lysate was incubated with 100 μM CyCl at 4 °C for 4 h and divided into ten groups of 50 μL each. The samples were incubated at a temperature gradient of 37,41,45,49,53,57,61,65,69, and 73 °C for 4 min, cooled at room temperature for 3 min, then centrifuged at 12 000 g for 10 min at 4 °C. The supernatant was collected and analyzed by western blotting.…”

Identification Drug Targets for Oxaliplatin-Induced Cardiotoxicity without Affecting Cancer Treatment through Inter Variability Cross-Correlation Analysis (IVCCA)

“…Patients treated with oxaliplatin often experience rapid breathing, chest pain, tachycardia, and arrhythmias. Although emergency situations in oxaliplatin-treated patients are relatively rare compared to other drugs like anthracyclines (18,19) or 5-fluorouacil (20), it is a rising concern given the increasing number of patients treated with oxaliplatin alone or in combination with other drugs. A growing number of cases related to severe coronary and cardiotoxicity of oxaliplatin alone (21,22) or together with 5-fluoruracil or FOLFOX (23)(24)(25)(26) have been reported.…”