Abstract 2751: Protective effects of phenylaminoethyl selenide (PAESe) on doxorubicin-induced cardiotoxicity in vitro and in vivo

Abstract

Abstract Anthracyclines are potent anticancer agents that are effective in the treatment of acute leukemia, non-Hodgkin's lymphomas, breast, ovarian and lung cancers, but their clinical use is hampered by dose-limiting cardiotoxicity mediated by free radicals generation. We determined the ability of phenyl-2-aminoethyl selenide (PAESe), a novel antioxidant, to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe on human breast carcinoma (BT-474) and prostate adenocarcinoma (PC-3) cells were determined alone and in combination with two clinically used anticancer agents, DOX, a topoisomerase-2 antagonist known to generate reactive oxygen species (ROS), and vincristine (a tubulin binding agent) and a known oxidant, tert-butylhydroperoxide (TBHP). Conventional growth inhibitory assays, i.e., sulforhodamine B (SRB) and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) staining, were used to determine in vitro activity. Treatment effect on intracellular formation of ROS was also determined by quantifying the oxidation of a cell-permeant indicator H2DCFDA. The effect of PAESe on cardiomyocytes was determined in NCr (nu/nu) mice with DOX (5 mg/kg), PAESe (10 mg/kg), concomitant (DOX & PAESe) therapy, and saline controls were administered by tail vein injections weekly over 12 weeks. Histopathological examination was performed to look for evidence of cardiotoxicity. PAESe did not alter the growth of BT-474 or PC-3 cells up to 10 uM. However, co-administration of PAESe decreased the oxidative-mediated cytotoxicity of TBHP in a dose-dependent manner, but had limited to no effect on vincristine or DOX antitumor activity. Further, PAESe decreased the formation of intracellular ROS from TBHP and DOX in a dose-dependent manner. Histological examination showed PAESe decreased short-term DOX-mediated infiltration of neutrophils and macrophages into the myocardium and more chronic evidence of necrotic foci, suggesting PAESe decreased early and late myocardial damage following initial and prolonged DOX treatments, unlike other antioxidants. Concomitant administration of PAESe did not alter the antitumor activity of DOX in vivo, nor did it reduce treatment mediated weight-loss associated with DOX. These data suggest that PAESe may be used in combination with DOX to preserve its antitumor activity, but decrease free radical generation and cardiotoxicity associated with use of anthracyclines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2751. doi:1538-7445.AM2012-2751