The interplay between doxorubicin chemotherapy, antioxidant system, and cardiotoxicity: Unrevealing of the protective potential of tannic acid

Abstract

Cardiotoxicity is the leading side effect of anthracycline-based chemotherapy. Therefore, it has gained importance to reveal chemotherapy-supporting strategies and reliable agents with their mechanisms of action. Tannic acid (TA), a naturally occurring plant polyphenol, has diverse physiological effects, including anti-inflammatory, anticarcinogenic, antioxidant, and radical scavenging properties. Therefore, this study was designed to investigate whether TA exerts a protective effect on mechanisms contributing to anthracycline-induced cardiotoxicity in rat heart tissues exposed to doxorubicin (DOX). Rats were randomly divided into control and experimental groups and treated with (18 mg/kg) DOX, TA (50 mg/kg), and DOX + TA during the 2 weeks. Cardiac gene markers and mitochondrial DNA (mtDNA) content were evaluated in the heart tissues of all animals. In addition to major metabolites, mRNA expression changes and biological activity responses of components of antioxidant metabolism were examined in the heart tissues of all animals. The expression of cardiac gene markers increased by DOX exposure was significantly reduced by TA treatment, whereas mtDNA content, which was decreased by DOX exposure, was significantly increased. TA also improved antioxidant metabolism members' gene expression and enzymatic activity, including glutathione peroxidase, glutathione s-transferase, superoxide dismutase, catalase, and thioredoxin reductase. This study provides a detailed overview of the current understanding of DOX-induced cardiotoxicity and preventive or curative measures involving TA.

Keywords: antioxidant system; cardiotoxicity; doxorubicin; heart; tannic acid.

FIGURE 1

In vivo experimental study protocol. CON group was injected with saline (placebo) daily. Doxorubicin (DOX) injection was performed on Days 1, 3, 5, 8, 10, and 12. The tannic acid (TA) group was injected with TA for 14 consecutive days. The same administration as the DOX and TA groups was performed on the DOX + TA group.

FIGURE 2

mRNA expression of cardiac gene markers in the heart tissues of the control versus treated groups. (A) The relative mRNA expression levels of Anp. (B) The relative mRNA expression levels of Bnp. (C) The relative mRNA expression levels of β‐Mhc. (D) Mitochondrial DNA (mtDNA) copy number after doxorubicin (DOX) or tannic acid (TA) treatment, quantified by quantitative PCR (qPCR) relative to the nuclear genome. “ns” represents p > 0.05, “*” represents p < 0.05, “**” represents p < 0.01, “***” represents p < 0.001, and “****” represents p < 0.0001 versus control group. The data are shown as mean ± SEM (n = 5).

FIGURE 3

Malondialdehyde (MDA) levels and reduced glutathione (GSH) content in the rat heart tissues. MDA levels in liver tissues (A) and comparison of GSH content (B). “ns” represents p > 0.05, “*” represents p < 0.05, and “**” represents p < 0.01 versus control group. The data are shown as mean ± SEM (n = 5).

FIGURE 4

Effects of doxorubicin (DOX) and tannic acid (TA) on the mRNA expression and specific activities of antioxidant metabolism members in the rat heart tissues. The relative mRNA expressions of Gpx, glutathione peroxidase (A); Gst, glutathione s‐transferase (C); Cat, catalase (E); Sod, superoxide dismutase (G); and Txnrd2, thioredoxin reductase 2 (I). The enzymatic activities of GPx (B), GST (D), CAT (F), SOD (H), and TRXR (J) after saline, TA, DOX, and DOX + TA treatment. “ns” represents p > 0.05, “*” represents p < 0.05, “**” represents p < 0.01, “***” represents p < 0.001, and “****” represents p < 0.0001 versus control group. The data are shown as mean ± SEM (n = 5).