Synthetic antioxidant TS-13 reduces doxorubicin cardiotoxicity

Abstract

The antitumor antibiotic doxorubicin, a representative of a large group of anthriacyclines, is widely and quite effectively used to treat patients with malignant neoplasms. The aim of this study was to study the effect of TS-13, a synthetic phenolic antioxidant and an activator of the antioxidant-responsive element redox-sensitive signaling system Keap1/ Nrf2/ARE, on the functional parameters of an isolated rat heart after a course of doxorubicin administration. Material and methods. Male Wistar rats (n = 24) were divided into three groups: control (n = 10), doxorubicin group (n = 7) (3 weekly intraperitoneal injections of doxorubicin solution at a cumulative dose of 15 mg/kg) and doxorubicin + TS-13 (n = 7) (administration of doxorubicin according to a similar scheme, TS-13 solution with drinking water). On the 21st day after the start of the experiment, the cardioprotective effect of TS-13 was assessed on the ex vivo model of perfusion of the heart isolated according to Langendorff. Coronary flow, heart rate (HR), pressure in the left ventricle (myocardial contractility) were recorded as parameters of myocardial functional activity; the integral indicator of myocardial contractility (working capacity) was calculated as the product of HR and pressure in the left ventricle. Results and discussion. The general toxic effect of doxorubicin was manifested in a significant decrease in rat body weight (by 21 %), the administration of TS-13 reduced the cachectic effect of the cytostatic. Doxorubicin worsened heart work by all studied parameters (coronary flow, HR, myocardial contractility and integral index of contractility); the effect persisted throughout the entire perfusion period (40 min). Animals treated with intraperitoneal injections of doxorubicin and TS-13 per os lost weight to a lesser extent, the functional activity of isolated hearts improved significantly – coronary flow, pressure in the left ventricle, and working capacity increased. Conclusions. Since, as we have shown earlier, TS-13 administration not only does not cancel, but even potentiates the antitumor activity of doxorubicin, the results obtained indicate the promise of using TS-13 as an adjuvant therapy for malignant neoplasms, enhancing the antitumor effect of the cytostatic and leveling its side effects, including cardiotoxicity.

Keywords

• doxorubicin
• isolated heart
• rats
• cardiotoxicity
• oxidative stress
• antioxidants
• keap1/nrf2/are signaling system