Transcriptome Profiling of Peripheral Blood Cells Identifies Potential Biomarkers for Doxorubicin Cardiotoxicity in a Rat Model

Valentina K Todorova,V Suzanne Klimberg,Ishwori Dhakal,Jeanne Y Wei,Robert R Delongchamp,Marjorie L Beggs,Issam Makhoul,Qing Song

doi:10.1371/journal.pone.0048398

Abstract

AimsDoxorubicin (DOX), a widely used anticancer agent, can cause an unpredictable cardiac toxicity which remains a major limitation in cancer chemotherapy. There is a need for noninvasive, sensitive and specific biomarkers which will allow identifying patients at risk for DOX-induced cardiotoxicity to prevent permanent cardiac damage. The aim of this study was to investigate whether the expression of specific genes in the peripheral blood can be used as surrogate marker(s) for DOX-induced cardiotoxicity.Methods/ResultsRats were treated with a single dose of DOX similar to one single dose that is often administered in humans. The cardiac and peripheral blood mononuclear cells (PBMCs) genome-wide expression profiling were examined using Illumina microarrays. The results showed 4,409 differentially regulated genes (DRG) in the hearts and 4,120 DRG in PBMC. Of these 2411 genes were similarly DRG (SDRG) in both the heart and PBMC. Pathway analysis of the three datasets of DRG using Gene Ontology (GO) enrichment analysis and Ingenuity Pathways Analysis (IPA) showed that most of the genes in these datasets fell into pathways related to oxidative stress response and protein ubiquination. IPA search for potential eligible biomarkers for cardiovascular disease within the SDRG list revealed 188 molecules.ConclusionsWe report the first in-depth comparison of DOX-induced global gene expression profiles of hearts and PBMCs. The high similarity between the gene expression profiles of the heart and PBMC induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity. Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and ultimately to allow individualized anti-cancer therapy.

Highlights

Doxorubicin (DOX, Adriamycin) is the key component of many cytotoxic regimens for treatment of different adult and childhood cancers [1]
The high similarity between the gene expression profiles of the heart and peripheral blood mononuclear cells (PBMCs) induced by DOX indicates that the PBMC transcriptome may serve as a surrogate marker of DOX-induced cardiotoxicity
Future directions of this research will include analysis of PBMC expression profiles of cancer patients treated with DOX-based chemotherapy to identify the cardiotoxicity risk, predict DOX-treatment response and to allow individualized anti-cancer therapy

Summary

Introduction

Doxorubicin (DOX, Adriamycin) is the key component of many cytotoxic regimens for treatment of different adult and childhood cancers [1]. The clinical methods used for detection of presymptomatic DOX-induced cardiotoxicity [assessment of left ventricular volume (LVV) and ejection fraction (LVEF) using echocardiography and radionuclide angiography] show low diagnostic sensitivity and low predictive power, and identify the existing cardiomyopathy rather than prevent it [14],[15]. Invasive techniques such as endomyocardial biopsy cannot be performed routinely [16]. Blood cardiac biomarkers such as cardiac troponins [17] and cardiac natriuretic peptides [18] have been evaluated in animal models and in clinical studies [19] but their diagnostic and prognostic values in humans have not been validated [20]

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Conclusion