Protection from Doxorubicin-Induced Cardiomyopathy Using the Modified Anthracycline N-Benzyladriamycin-14-valerate (AD 198)

Abstract

The anthracycline doxorubicin (Dox) is an effective antitumor agent. However, its use is limited because of its toxicity in the heart. N- ) is a modified anthracycline with antitumor efficacy similar to that of Dox, but with significantly less cardiotoxicity and potentially cardioprotective elements. In the present study, we investigated the possibility of in vivo protective effects of low-dose AD 198 against Dox-induced cardiomyopathy. To do this, rats were divided into four groups: vehicle, Dox (20 mg/kg; single injection day 1), AD 198 (0.3 mg/kg per injection; injections on days 1, 2, and 3), or a combination treatment of Dox ϩ AD 198. Seventy-two hours after beginning treatment, hearts from the Dox group had decreased phosphorylation of AMP kinase and troponin I and reduced poly(ADP-ribose) polymerase, ␤-tubulin, and serum albumin expression. Dox also increased the phosphorylation of phospholamban and expression of inducible nitric-oxide synthase in hearts. Each of these Dox-induced molecular changes was attenuated in the Dox ϩ AD 198 group. In addition, excised hearts from rats treated with Dox had a 25% decrease in left ventricular developed pressure (LVDP) and a higher than normal increase in LVDP when perfused with a high extracellular Ca 2ϩ solution. The Dox-induced decrease in baseline LVDP and hyper-responsiveness to [Ca 2ϩ ] was not observed in hearts from the Dox ϩ AD 198 group. Thus Dox, with well established and efficient antitumor protocols, in combination with low levels of AD 198, to counter anthracycline cardiotoxicity, may be a promising next step in chemotherapy.

Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: A mitochondrial division/mitophagy inhibitor

“…Doxorubicin has previously been found to reduce both left ventricular developed pressure and heart rate, also shown in this study [15,34,35]. Interestingly, the presented data show that doxorubicin treatment in the naïve hearts caused a drop in the heart rate readings as opposed to its effects in conditions of ischaemia and reperfusion injury where no significant decrease in the heart rate values were recorded.…”

Antitumour Anthracyclines: Progress and Perspectives

“…Specifically, it activates PKC‐δ which is subjected to proteolysis by caspases‐3 involved in the promotion and intensification of the apoptotic signals with the aid of activation of p38 signalling pathway and fragmentation of PARP . In contrast to doxorubicin, compound 24 proved to be non‐cardiotoxic in rodent model through activation of the PKC‐ϵ pathway in cardiomyocytes …”

Design, Development, Characterization and Testing of CD22 Targeted Long Circulating Liposomal Drug Delivery Systems for B Cell Malignancies

“…Nbenzyladriamycin-14-valerate (AD 198) is a newer lipophilic anthracycline, which is superior to doxorubicin (DOX) in murine cancer models and has novel biochemical pathways and pharmacological properties (He et al, 2005). It has been shown that the cells that had developed (multiple drug resistance) MDR toward DOX, were sensitive to AD 198 (Cai et al, 2010, Ganapathi et al, 1989. The cardiotoxicity manifested by DOX is also absent in AD 198 and that was one of the rationales for AD 198 development.…”

“…AD 198 does not display the cardiotoxic property of doxorubicin. Moreover, it is cardioprotective to the cardiomyocytes from the damage caused by doxorubicin therapy (Cai et al, 2010). Previously it was known that the cardiotoxicity of doxorubicin is due to the generation of reactive oxygen species (ROS) from the semi-quinone ring.…”