Comparative Cardiac Toxicity of Anthracyclines In Vitro and In Vivo in the Mouse

Stefano Toldo,Norbert F Voelkel,Giuseppe G L Biondi-Zoccai,Rachel W Goehe,Giovanni Palazzoni,Eleonora Mezzaroma,David A Gewirtz,Marzia Lotrionte,Francesco Loperfido,Ignacio M Seropian,Evan T Sumner,Benjamin W Van Tassell,Antonio Abbate

doi:10.1371/journal.pone.0058421

Abstract

PurposeThe antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo.MethodsThe cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment.ResultsIn HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin.ConclusionThis study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

Highlights

Advances in the treatment of cancer improved cancer-free survival and highlighted the occurrence of previously unrecognized complications such as secondary neoplasms and off-target organ toxicity [1,2,3,4]
To better characterize the mechanisms of cardiotoxicity and the differences between the three anthracyclines, we evaluated the effects of a non-pegylated liposomal-delivered doxorubicin formulation in comparison with standard doxorubicin as well as epirubicin on cardiomyocytes in culture in vitro and on cardiac systolic function, heart rate (HR) and cardiac output (CO) in the mouse in vivo
Epirubicin and doxorubicin produced a significantly greater degree of Reactive oxygen species (ROS) generation compared to controls (70- and 50-fold respectively) and compared to the non-pegylated liposomal doxorubicin (20-fold vs control) (Figure 1)

Summary

Introduction

Advances in the treatment of cancer improved cancer-free survival and highlighted the occurrence of previously unrecognized complications such as secondary neoplasms and off-target organ toxicity [1,2,3,4]. Doxorubicin and epirubicin are the most commonly used anthracyclines [5,6,7]. Epirubicin has been proposed as an alternative to doxorubicin because of reportedly lesser cardiac toxicity [8]. A novel liposomal-delivered doxorubicin formulation (MyocetTM), which has been introduced recently, has been associated with reduced cardiac toxicity [8]. One clinical study has suggested that epirubicin and liposomal doxorubicin have similar cardiotoxic profiles [13]. The LITE study [Liposomal doxorubicin–Investigational chemotherapy–Tissue doppler imaging] is another recently completed clinical trial in patients with breast cancer randomized to a non-pegylated liposomal-doxorubicin-based or epirubicinbased chemotherapy regimen to determine the incidence of clinical and subclinical cardiotoxicity using Tissue Doppler Analysis [14,15]

Methods

Results

Conclusion