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Extracellular Vesicles Released By Published OnlineFirst October 25, 2017; DOI: 10.1158/1078-0432.CCR-17-2046 Cancer Therapy: Preclinical Clinical Cancer Research Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury Chontida Yarana1,2, Dustin Carroll1, Jing Chen3, Luksana Chaiswing1, Yanming Zhao1, Teresa Noel1, Michael Alstott4, Younsoo Bae5, Emily V. Dressler6, Jeffrey A. Moscow7, D. Allan Butterfield4,8, Haining Zhu1,3,4, and Daret K. St. Clair1 Abstract Purpose: Cardiac injury is a major cause of death in cancer tinctive presence of brain/heart, muscle, and liver isoforms of survivors, and biomarkers for it are detectable only after tissue glycogen phosphorylase (GP), and their origins were verified to injury has occurred. Extracellular vesicles (EV) remove toxic be heart, skeletal muscle, and liver, respectively. The presence of biomolecules from tissues and can be detected in the blood. brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of Here, we evaluate the potential of using circulating EVs as early PYGB in heart, but not brain tissues. Manganese superoxide dis- diagnostic markers for long-term cardiac injury. mutase (MnSOD) overexpression, as well as pretreatment with Experimental Design: Using a mouse model of doxorubicin cardioprotective agents and MnSOD mimetics, resulted in a reduc- (DOX)-induced cardiac injury, we quantified serum EVs, analyzed tion of EV-associated PYGB in mice treated with DOX. Kinetic proteomes, measured oxidized protein levels in serum EVs released studies indicated that EVs containing PYGB were released prior to after DOX treatment, and investigated the alteration of EV content. the rise of cardiac troponin in the blood after DOX treatment, Results: Treatment with DOX caused a significant increase in suggesting that PYGB is an early indicator of cardiac injury. circulating EVs (DOX_EV) compared with saline-treated controls. Conclusions: EVs containing PYGB are an early and sensitive DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644–53. Ó2017 proteins, a lipid peroxidation product linked to DOX-induced AACR. cardiotoxicity. Proteomic profiling of DOX_EVs revealed the dis- See related commentary by Zhu and Gius, p. 1516 Introduction survived their cancer, these patients may unfortunately suffer from complications of treatment, ranging from non-fatal condi- Chemotherapy can damage normal cells as well as cancer cells tions such as cognitive dysfunction, neuropathy, and infertility, to and can therefore result in late onset of side effects that compro- life-threatening conditions such as cardiomyopathy, myelodys- mise patient survivorship and quality of life. According to the plastic syndrome, and secondary malignancy (2). Severe adverse American Cancer Society's Surveillance and Health Services effects of chemotherapy can also have a substantial economic Research, as of 2014, around 6 million cancer survivors had lived impact due to hospitalizations and prescriptions, costs for which longer than 10 years since their diagnosis (1). Although they are estimated at around $12,907 and $1,908 per person per year, respectively (3). This estimation reaffirms the significance of preventing cancer treatment-related adverse effects. 1Department of Toxicology and Cancer Biology, University of Kentucky, Lex- 2 With the exception of secondary malignancies, cardiovascular ington, Kentucky. Faculty of Medical Technology, Mahidol University, Salaya, disease is the leading cause of death among cancer survivors (4). Thailand. 3Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky. 4Markey Cancer Center, Redox Metabolism Anthracyclines, especially doxorubicin (DOX), are the most com- Shared Resource Facility, University of Kentucky, Lexington, Kentucky. 5Depart- mon chemotherapeutic agents that cause cardiomyopathy. How- ment of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky. ever, their effectiveness and broad efficacy against more types of 6Division of Biostatistical Sciences, Wake Forest School of Medicine, Winston- cancer than any other class of chemotherapy make anthracyclines Salem, North Carolina. 7Investigational Drug Branch, National Cancer Institute, 8 a frequently used drug class (5). Bethesda, Maryland. Department of Chemistry, University of Kentucky, Lex- DOX-induced cardiomyopathy presents as a decline of left ington, Kentucky. ventricular function that can develop many years after treatment Note: Supplementary data for this article are available at Clinical Cancer cessation (6). Cardiac troponin-I (cTnI) and troponin-T (cTnT) Research Online (http://clincancerres.aacrjournals.org/). are validated serological biomarkers for DOX-induced cardiotoxi- Corresponding Author: Daret K. St. Clair, University of Kentucky, 454 Bosom- city. Although these biomarkers are specific in predicting adverse worth HSRB, 1095 VA Drive, Lexington, KY 40536. Phone: 859-257-3956; Fax: outcomes from high-dose radiation and chemotherapy, the evi- 859-323-1059; E-mail: [email protected] dence for low and moderate doses, as well as in asymptomatic doi: 10.1158/1078-0432.CCR-17-2046 childhood cancer survivors, remains unclear (7, 8). Moreover, Ó2017 American Association for Cancer Research. they are released after cardiac cell death occurs, which is not an 1644 Clin Cancer Res; 24(7) April 1, 2018 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst October 25, 2017; DOI: 10.1158/1078-0432.CCR-17-2046 EVs Contain a Sensitive Protein Barcode Detectable in Blood However, little is known about the oxidative status, content, or Translational Relevance tissue origin for circulating EVs generated by chemotherapy- Significant advances in the efficacy of cancer therapy have induced tissue injury. been accompanied by an escalation in side effects that result In the present study, we investigated the protein content of EVs from therapy-induced injury to normal tissues. The number of to determine the potential profile for early detection of cardiac cancer survivors is now 14.5 million in the United States alone injury after DOX treatment. We found that EVs present after DOX and is expected to rise by 31% to 19 million by 2024 (www. treatment contained signatures of cardiac tissue and high levels cancer.org). Cardiac injury is a major cause of death in cancer of protein-bound 4-hydroxynonenal (4HNE), which can be survivors, but the current indicators of cardiac injury are alleviated by enhancing tissue antioxidant capacity. Moreover, detectable only after significant damage has occurred. Thus, the EVs and their protein contents are more sensitive than con- sensitive biomarkers are needed to permit early intervention to ventional serological biomarkers for detection of DOX-induced prevent long-term cardiac injury after chemotherapy. In tissue injury. response to stress conditions, tissues release extracellular vesi- cles into circulation. The presence of tissue-specific glycogen phosphorylase in circulating extracellular vesicles and the Materials and Methods reduction of glycogen phosphorylase, brain (PYGB) in cardiac Animals and treatment tissue following chemotherapy makes it a clinically attractive Male C57BL/6J mice 10 to 12 weeks of age and 25 to 28 g in diagnostic biomarker for therapeutic interventions. body weight were injected intraperitoneally (IP) with a single 20 mg/kg dose of doxorubicin hydrochloride (DOX; Bedford Laboratories, Inc.) or saline (SAL). All mouse-related procedures followed the American Veterinary Medical Association Guidelines early event in the development of chemotherapy-induced cardi- for the Care and Use of Laboratory Animals and were approved by otoxicity. Thus, it is not optimal to start cardioprotective inter- the Institutional Animal Care and Use Committee at the Univer- ventions based on cTnI or cTnT levels. sity of Kentucky. Blood was collected at 1, 24, 48, and 72 hours DOX-induced cardiotoxicity and other normal tissue injury after treatment. To avoid heart tissue injury during blood collec- begin with the generation of reactive oxygen species (ROS) and tion, we collected blood from the inferior vena cava. Blood was reactive nitrogen species (RNS), predominantly in the mitochon- allowed to clot by incubation at room temperature for at least dria (9, 10). Excess ROS/RNS results in oxidative damage to 30 minutes. The clot was pelleted by centrifugation at 1,300 g biomolecules such as lipids, DNA, and proteins. Oxidative mod- for 15 minutes, and the serum was collected and stored at À80C. ification of lipids and proteins leads to mitochondrial dysfunction For the indicated experiments, dexrazoxane (DRZ; Zinecard, (11) and consequently activates cell death pathways (12). To and Upjohn Company LLC, Division of Pfizer Inc.) was admin- maintain cellular homeostasis, the cells can remove oxidized istered at 200 mg/kg IP 30 minutes before DOX treatment as proteins in several ways, e.g., through ubiquitin/proteasome- recommended in the clinical use guide (21). The manganese mediated degradation, autophagy, and extracellular vesicles (EV). superoxide dismutase (MnSOD) mimetic Mn(III) meso-tetrakis However, recent evidence has shown that extensive and sustained (N-(n-butoxyethyl)pyridium-2-yl)porphyrin, MnTnBuOE-2- þ oxidative stress during chemotherapy impairs cellular ability to PyP5 (MnP) was kindly provided by Dr. Ines Batinic-Haberle
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