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

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.

Spectroscopic studies of anthracyclines: Structural characterization and in vitro tracking

“…The impact on cells of DOX exposure has been assessed in various in vitro tests [14,17,[48][49][50]. Spectroscopic methods have also been employed to study the interactions in vitro [25,[51][52][53].…”

“…Inhibition of topoisomerase II in cancer cells consists of the formation of the complex of anthracycline-DNA-topoisomerase II, 4 resulting in DNA fragmentation and, as a consequence, in the inhibition of cellular proliferation and cell death [1,8,9]. Anthracycline therapy is complicated by its cardiotoxicity, which can in some cases lead to symptomatic heart failure, and even death caused by cardiac diseases (Torti et al 1986 Toldo et al 2013). These complications can occur both during active anti-cancer therapy (so called early cardiotoxicity), within one year after the end of treatment, and many years after the end of therapy with anthracyclines [18,19].…”

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

“…However, DOX-based chemotherapy is characterized by poor tumor selectivity plus severe (dose-limiting) side effects in healthy tissues and cells. 3,4 Furthermore, DOX can lead to drug resistance in breast cancer cells, which may be another pertinent cause of chemotherapy failure. 5 Therefore, new research efforts are needed to reduce the effective dose required for antitumor activity, the toxicity, and the drug resistance associated with DOX in such chemotherapy programs.…”

Teraphtal (sodium salt of cobalt 4,5-carboxyphthalocyanine) Decreases Sensitivity of Tumor Cells to Anthracycline Antibiotics and Mitoxantrone in Vitro

“…Возможно ли образование АФК при концентрациях АА, достигаемых в клинике (≤ 1 мкмоль/л) [13], -не-известно. Тем не менее роль АФК в токсичности АА признается для ряда нормальных клеток, включая кардиомиоциты [14] и тромбоциты [15], и остается гипотетической для опухолевых клеток человека, растущих in vitro [14,16,17].…”