Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity

Abstract

Improvements in long-term cancer survival rates have resulted in an increase in the prevalence of chemotherapylinked cardiac failure, but treatment-induced cardiac injuries may not be detected until long after therapy. Monitoring cardiac function is recommended; however, cardiovascular injury in cancer patients differs from those with primary cardiac dysfunction, which limits the utility of traditional cardiac biomarkers. Here we examined plasma levels of peptides produced by cathepsin B, which is released during chemotherapy-induced cardiac injury. We applied nanotrap fractionation to enrich plasma peptides from cancer patients treated with or without chemotherapy. Peptides associated with chemotherapyinduced cardiotoxicity, but not other cardiac injury, were identified by mass spectrometry, and their dependence on cathepsin B activity was determined using enzyme inhibition experiments. We found that a peptide (SAA-1525) derived from serum amyloid A1 was significantly increased in cardiotoxicity patients, and its production was inhibited when plasma samples were pretreated with cathepsin B specific inhibitors. Plasma SAA-1525 also correlated with other markers of cardiac injury. Analysis of plasma SAA-1525 levels may hold potential as a rapid and minimally invasive method to monitor subclinical injury, thereby allowing timely intervention to mitigate further cardiac damage and avoid more severe clinical presentation.

Circulating biomarkers for management of cancer therapeutics-related cardiac dysfunction

“… 127 However, it is worth noting that sample numbers were small for both the discovery and validation studies. Zhang et al 128 investigated peptide-level changes associated with cathepsin-B release in response to treatment with Gemcitabine and 5-fluorouracil. Cathepsin-B mediates inflammasome activation and is required for doxorubicin-induced cardiomyocyte cell death.…”

“…MS-based analysis of the plasma proteome led to the identification of a novel candidate peptide biomarker SAA-1525 that was significantly elevated in patients with CTRCD, independently of inflammation-induced cardiac damage, through proteolytic activity of cathepsin-B. 128 In addition to causing changes in protein expression levels, chemotherapy can also modulate protein activity. MS offers a means to investigate this by identifying and measuring protein phosphorylation events.…”

Innovation and Discovery in Cardiovascular Biology

“…They discovered multiple molecular pathways, encompassing several druggable enzymes, that either enhance or inhibit cardiomyocyte necrosis, thereby offering a rich data set of clinically relevant targets for cardiac ischemia. Zhang et al 4 tackled the complex problem of cardiotoxicity and cardiac failure following chemotherapy by performing a small-scale clinical study aimed at discovering better predictive markers of cardiotoxicity in patients treated with chemotherapy. Using nanotrap fractionation and mass spectometry of plasma, the group was able to enrich for plasma peptides produced by cathepsin B cleavage.…”