Synthetic Antioxidant TS-13 Reduces the Cardiotoxicity of Doxorubicin

Abstract

The antitumor antibiotic doxorubicin, a member of a large group of anthracyclines, is widely and quite effectively used to treat patients with malignant neoplasms. However, a serious side effect of this drug is cardiotoxicity, largely due to the anthracycline’s ability to induce oxidative stress. The purpose of this study was to study the effect of TS-13, a synthetic phenolic antioxidant and activator of the redox-sensitive signaling system of the antioxidant-responsive element Keap1/Nrf2/ARE, on the functional parameters of the isolated rat heart after a course of doxorubicin administration. Male Wistar rats (n = 24) were divided into three groups: control (n = 10); a “doxorubin” group (n = 7), which received three weekly intraperitoneal injections of doxorubicin solution at a cumulative dose of 15 mg/kg; and a “doxorubicin + TS-13” group (n = 7) (doxorubicin was administered according to a similar scheme; TS-13 solution, with drinking water). On the 21st day after the start of the experiment, the presence of a cardioprotective effect of TS-13 was assessed ex vivo using a Langendorff model of the isolated heart. As parameters of myocardial functional activity, coronary flow, heart rate, and pressure in the left ventricle (myocardial contractility) were recorded; the integral indicator of myocardial contractility (performance) was calculated as the product of heart rate and pressure in the left ventricle. The general toxic effect of doxorubicin manifested itself in the form of a significant decrease in the body weight of animals (by 21%), the administration of TS-13 reduced the cachectic effect of the cytostatic. Doxorubicin worsened cardiac function in all the studied parameters (coronary flow, heart rate, myocardial contractility and integral contractility index); the effect persisted throughout the entire period of perfusion (40 min). Animals that received TS-13 per os along with intraperitoneal injections of doxorubicin lost less weight, and the functional activity of isolated hearts significantly improved: coronary flow, pressure in the left ventricle, and performance increased. We have previously shown that the administration of TS-13 not only does not cancel, but even potentiates, the antitumor activity of doxorubicin. The results obtained indicate the prospects of using TS-13 as an adjuvant therapy for malignant neoplasms, enhancing the antineoplastic effect of the cytostatic and neutralizing its side effects, including cardiotoxicity.