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Year : 2021  |  Volume : 34  |  Issue : 1  |  Page : 333-339

Possible protective effects of quercetin on doxorubicin-induced cardiotoxicity in rats

1 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission08-Jan-2020
Date of Decision09-Feb-2020
Date of Acceptance14-Feb-2020
Date of Web Publication27-Mar-2021

Correspondence Address:
Fatma E. R. Hashish
Shebin Elkom, Menoufia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_5_20

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Our study aimed to investigate the possible protective effects of quercetin (QCT) on doxorubicin (DOX)-induced cardiotoxicity in rats.
DOX is an antineoplastic drug that produces cardiotoxicity; it generates highly cytotoxic-free radicals that damage the cardiomyocytes. QCT is a plant flavonoid. QCT pretreatment reduces DOX-induced oxidative stress.
Materials and methods
Fifty-five adult rats were divided into four groups: group 1 (control) received saline (5 ml/kg) orally for 4 weeks; group 2 (DOX) received six doses of DOX intraperitoneally (2.5 mg/kg) on alternative days in the last 2 weeks; group 3 (QCT + DOX) received QCT orally (10 mg/kg once daily) for 4 weeks and DOX intraperitoneally (2.5 mg/kg) in the last 2 weeks as group 2, and group 4 (QCT) received QCT (10 mg/kg once daily) orally for 4 weeks. We measured the body weight, heart weight, and ECG parameters. Serum cardiac troponin-I (cTn-I), serum malondialdehyde (MDA), and total serum antioxidant capacity (TAC) have been estimated. In addition, histopathological changes of the rat heart were assessed.
The DOX group showed significant ECG changes, significant increase in serum cTn-I (P < 0.001) and MDA (P < 0.001), significant decrease in TAC (P < 0.001), pathological picture of cardiomyopathy by hematoxylin and eosin staining, and high apoptotic index (P < 0.001) by caspase-3 stain compared with the control group. QCT pretreatment improved ECG changes, significantly decreased serum cTn-I (P < 0.001) and MDA (P < 0.001), significantly increased serum TAC (P < 0.001), and improved histopathological changes of the heart with significant lower apoptotic index (P < 0.001) compared with the DOX group.
QCT may be a promising cardioprotective agent against DOX-induced cardiotoxicity due to its inhibition of cardiac apoptosis and oxidative stress.

Keywords: apoptosis, cardiotoxicity, doxorubicin, oxidative stress, quercetin

How to cite this article:
Hashish FE, Abdel-Wahed MM, El-Odemi MH, El-Naidany SS, ElBatsh MM. Possible protective effects of quercetin on doxorubicin-induced cardiotoxicity in rats. Menoufia Med J 2021;34:333-9

How to cite this URL:
Hashish FE, Abdel-Wahed MM, El-Odemi MH, El-Naidany SS, ElBatsh MM. Possible protective effects of quercetin on doxorubicin-induced cardiotoxicity in rats. Menoufia Med J [serial online] 2021 [cited 2021 Oct 23];34:333-9. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/333/312053

  Introduction Top

Doxorubicin (DOX) is an anthracycline antibiotic; it is commonly used to treat many types of cancer like breast cancer, bladder cancer, lymphoma, and acute lymphocytic leukemia. There is a limitation of DOX use due to its severe and feared adverse effects to the heart, kidney, and the liver. Cardiotoxicity induced by DOX is dose dependent. The incidence of DOX-induced cardiotoxicity ranges from greater than 4% in patients receiving a cumulative dose of 500–550 mg/m2 to more than 36% at a cumulative dose more than or equal to 601 mg/m2 [1].

There are numerous studies that have shown that the damaging effects of DOX on cardiomyocytes are due to mitochondrial dysfunction, the production of reactive oxygen species (ROS), such as 'superoxide, hydrogen peroxide, and hydroxyl radicals' [2] and the induction of cardiomyocyte apoptosis. Cardiomyocytes are more vulnerable to free radical-mediated damage induced by DOX as these cells have relatively low levels of antioxidant enzymes such as superoxide dismutase and catalase [3]. So, the heart can be protected from DOX-induced cardiotoxicity by qualifying the ROS generated by DOX in cardiomyocytes [4].

Quercetin (QCT) is an important dietary flavonoid that is present in many fruits and vegetables. In addition, it has antioxidant, anti-inflammatory and anticancer properties. QCT scavenges superoxide anion, singlet oxygen, and lipid peroxy radicals [5]. It was found in several reports that QCT scavenges ROS and inhibits the activation of extracellular signal-regulated kinase and mitogen-activated protein kinase in ROS-mediated cardiomyopathy [6].

So, this study aimed to investigate the possible protective effect of pretreatment with QCT on DOX-induced cardiotoxicity in rats.

  Materials and methods Top

QCT powder was purchased from Acros (4823 Newton Dr, Carlsbad, CA, USA). DOX vial from EMIC United Pharmaceuticals Co. EMIC (Badr, Cairo governorate) / Biopac (California, USA). (Egypt). Biochemicals and substrates were purchased from Biodiagnostic (Cairo, Egypt).

Fifty-five young adult male Sprague–Dawley albino rats weighting 150–200 g were purchased from a local vendor. Animals were housed in cages (five rats/cage) at room temperature throughout the experiment. The animals were fed with standard chow and water ad libitum. All experiments were carried out in accordance with protocols approved by the Local Ethics Committee for Animal Research in Faculty of Medicine, Menoufia University and complied with the Guide for the Care and Use of Laboratory Animals (ILAR 1996).

During the treatment period, out of the 55 rats, four rats from the DOX group, two rats from the QCT + DOX group, and two rats from the QCT group died. No deaths were observed within the control group. Data were collected from 10 animals per group. Rats were divided into four groups. Group 1 (control) received saline in at a dose of 5 ml/kg orally by an orogastric tube for 4 weeks. Group 2 (DOX group) received DOX in at a dose of 2.5 mg/kg; on alternate day injections for 2 consecutive weeks to achieve an accumulative dose of 15 mg/kg intraperitoneally in the last 2 weeks [7]. Group 3 (QCT + DOX group) received QCT (10 mg/kg; once daily) dissolved in 2 ml normal saline orally by an orogastric tube for 2 weeks in the first 2 weeks [8]. After that, they received QCT orally and DOX intraperitoneally for another 2 consecutive weeks in the last 2 weeks. Group 4 (QCT group) received QCT (10 mg/kg; once daily) dissolved in 2 ml normal saline orally by an orogastric tube for 4 weeks. Body weight of rats was measured at the beginning, after 2 weeks, and at the end of the experiment. In addition, the hearts were weighted after the rats were killed, then heart/body weight index was calculated (index = heart weight per grams divided by body weight per kilograms) [9]. After the last DOX treatment by 24 h, ECG was performed on all rats by Biopac ECG apparatus (Biopac Lab System, MP36R Unit and Acknowledge 5 Software, California, USA). The rat was placed on the surface of the block board so that its feet were not in contact with each other. The rat was kept in stationary position by securing their body by Velcro is the name of the company that manufactures the fastener used “the brand name”. present in United Kingdom. Disk electrodes were tied on the palmer surface of rat limbs. The front limbs and left hind limbs were used for the recording of ECG in standard leads, while the right hind limb was attached with the grounded electrode. ECG was recorded from which the heart rate (HR) and QT interval were measured [10]. After that, the blood samples were collected for serum separation and estimation of cardiac troponin-I (cTn-I), malondialdehyde (MDA), and total serum antioxidant capacity (TAC). In addition, histopathological changes of the rat heart were assessed by hematoxylin and eosin (H and E) and immunohistochemical (IHC) staining to detect apoptotic cells.

Rats were anesthetized with diethyl ether. Blood samples were collected using plain tubes from the retro-orbital plexus of fasting rats. The tubes were left to clot to obtain the serum by centrifugation at 8000g for 10 min, then collected, and stored at −80°C till the time of analysis and used to estimate cTn-I, MDA, and TAC. cTn-I was determined using an enzyme-linked immunosorbent assay kit that was obtained from BioMerieux (St Louis, Missouri, USA) for quantitative estimation of cTn-I in the rat serum. Estimation of serum MDA was through the spectrophotometric measurement of the color generated because of the reaction of thiobarbituric acid with MDA in an acidic medium. Measurement of serum TAC was performed by the reaction of antioxidants in the sample with a known amount of exogenously provided hydrogen peroxide. Kits for estimating both MDA and TAC were obtained from Biodiagnostic.

Rats were killed by cervical decapitation. The hearts of rats were collected and weighted for the estimation of heart/body weight index, and then fixed in 10% formalin for histopathological evaluation. Heart sections were stained with H and E stain using the routine technique, and then were analyzed qualitatively under a light microscope (Olympus Soft Imaging Solution GmbH, Mun-ster, Germany) (at 100×) for various histopathological alterations. In addition, IHC staining of apoptotic cells was carried out. Apoptotic cells were detected by polyclonal rabbit antihuman caspase-3 antibody that was purchased from Pharmingen (San Diego, California, USA).

Cells were defined as apoptotic if the whole nuclear area of the cell was labeled positively. To estimate the apoptotic index (the percentage of apoptotic events in a given area), apoptotic cells were counted in 10 high-power fields and this figure was divided by 100 normal cells in the same high-power fields.

Results were collected, tabulated, and statistically analyzed using an IBM personal computer and statistical package for the social sciences (version 20; SPSS Inc., Chicago, Illinois, USA). The results are expressed as mean ± SEM. One-way analysis of variance followed by Tukey post-hoc test was used for comparisons between means of different groups or Kruskal–Wallis test (nonparametric method) was used, followed by Mann–Whitney post-hoc test. A P value less than 0.05 was considered statistically significant.

  Results Top

Weight measurement (g) of the studied groups showed that all rats gained weight in a similar manner in first 2 weeks of the experiment when measured at the beginning of the experiment and after 2 weeks. But after that till the end of the experiment, QCT + DOX group and DOX group started to lose weight with more loss in the DOX group than the QCT + DOX group. The DOX group significantly reduced the body weight compared with the control group with a mean value of body weight change (−23.70 ± 0.29 vs. 30.10 ± 0.25; P < 0.001). However, administration of QCT to rats significantly reduced body weight loss caused by DOX with a mean value of body weight change (−7.90 ± 0.23 vs. −23.70 ± 0.29; P < 0.001) compared with the DOX group [Table 1].
Table 1: Effect of quercetin on body weight change, heart weight, heart/body weight index, and ECG parameters in doxorubicin-induced cardiotoxicity in rats

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Heart weight (g) and heart/body weight index (g/kg) of the DOX group were significantly decreased compared with the control group (0.50 ± 0.009 vs. 0.89 ± 0.01 and 3.92 ± 0.05 vs. 4.98 ± 0.04; P < 0.001, respectively), while QCT treatment significantly increased heart weight and heart/body weight index compared with the DOX group (0.65 ± 0.007 vs. 0.50 ± 0.009 and 4.46 ± 0.02 vs. 3.92 ± 0.05; P < 0.001, respectively) [Table 1].

DOX has been found to induce alterations in ECG parameters (changes in HR, increase in T wave amplitude, elevation of the ST segment and prolongation of the QT interval).

Post-24 h after last dose of DOX, ECG was recorded for all rats. After that, HR (B/min) and QT interval (ms) were measured from ECG recordings. In our study, ECG showed significant bradycardia and prolonged QT interval in the DOX group compared with the control group (375.50 ± 1.05 vs. 428.40 ± 0.76 and 95.10 ± 0.89 vs. 71.80 ± 0.76, respectively, P < 0.001). However, QCT treatment significantly increased HR and decreased QT interval when compared with the DOX group (398.80 ± 0.93 vs. 375.50 ± 1.05 and 81.20 ± 0.71 vs. 95.10 ± 0.89, respectively, P < 0.001) [Table 1].

The mean level of serum cTn-I (ng/ml) of the DOX group was significantly increased when compared with the control group (0.254 ± 0.013 vs. 0.014 ± 0.001; P < 0.001). QCT treatment significantly reduced the mean level of serum cTn-I compared with the DOX group (0.130 ± 0.011 vs. 0.254 ± 0.013; P < 0.001) [Table 2].
Table 2: Effect of quercetin on biochemical parameters and apoptotic index (immunohistochemical assessment of apoptosis by caspase-3) in doxorubicin-induced cardiotoxicity in rats

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The mean level of serum MDA (nmol/ml) of the DOX group was significantly increased when compared with the control group (58.80 ± 1.06 vs. 10.10 ± 0.95; P < 0.001). QCT treatment significantly reduced the mean level of serum MDA compared with the DOX group (29.80 ± 0.97 vs. 58.80 ± 1.06; P < 0.001) [Table 2].

The mean level of serum TAC (mM/l) of the DOX group was significantly decreased when compared with the control group (0.011 ± 0.001 vs. 0.085 ± 0.005; P < 0.001). QCT treatment significantly reduced the mean level of serum TAC compared with the DOX group (0.044 ± 0.002 vs. 0.011 ± 0.001; P < 0.001) [Table 2].

Histopathological assessment of cardiac tissues of rats in the different groups using the H and E and caspase-3 stains showed that control rats exhibited normal architecture and histology of cardiac tissues with the two stains used with negative caspase-3 staining [Table 3] and [Figure 1]a, [Figure 2]a.
Table 3: Effect of quercetin on histopathological (hematoxylin and eosin stain) parameters in doxorubicin-induced cardiotoxicity in rats

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Figure 1: Light microscopic examination of heart sections with H and E staining: (A) section of the control group showed normal cardiac muscle cells parallel to each other with a preserved structure; (B*) section of the DOX group showed inflammatory cell infiltration (plasma cells and lymphocytes) and muscle degeneration; (B**) section of the DOX group showed extensive hemorrhage and degeneration; (C*) section of the QCT + DOX group showed mild inflammatory infiltrate ‘lymphocytes;’ (C**) section of the QCT + DOX group showed mild degenerative changes; (D) section of the QCT group showed normal cardiomyocytes nearly similar to the control group (H and E, ×100 for A, B, C, and D). DOX, doxorubicin; H and E, hematoxylin and eosin; QCT, quercetin.

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Figure 2: Light microscopic examination of heart sections with IHC staining: (a) section of the control group showed negative caspase-3 staining; (b) section of the DOX group showed positive caspase-3 staining with a higher percentage of expression; (c) section of the QCT + DOX group showed positive caspase-3 staining with a lower percentage of expression; (d) section of the QCT group showed negative caspase-3 staining (caspase-3, ×100 for a and d, caspase-3, ×200 for b and c). DOX, doxorubicin; IHC, immunohistochemical; QCT, quercetin.

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In the DOX group, there were marked inflammation (10 rats; 40% of rat hearts have marked inflammation), marked hemorrhage (20%), marked degeneration (60%), congested blood vessels (10%), and focal necrosis (20%) as shown in H and E [Table 3] and [Figure 1]b*, [Figure 1]b**.

In the QCT + DOX group, there were mild inflammation (10 rats; 70% of rat hearts have mild inflammation) and mild degeneration (30%) with no hemorrhage, congested blood vessels, or necrosis [Table 3] and [Figure 1]c*, [Figure 1]c**.

DOX administration significantly increased the percentage of apoptotic cells [Figure 2]b and the apoptotic index (14.60 ± 1.0 vs. 1.20 ± 0.29; P < 0.001) [Table 2] as shown in caspase-3 stain. However, the QCT + DOX group showed less apoptotic cells [Figure 2]c and significant lower apoptotic index (4.50 ± 0.34 vs. 14.60 ± 1.0; P < 0.001) compared with the DOX group [Table 2].

There was no significant change in body weight, heart weight, heart/body weight index, and HR and QT intervals in the QCT group compared with the control group. Also, serum cTn-I, MDA, and TAC levels were normal. Histopathological examination of their hearts showed normal cardiac muscle appearance with no inflammation, degeneration, hemorrhage, or necrosis and with negative caspase-3 staining [Table 1], [Table 2], [Table 3] and [Figure 1]d, [Figure 2]d.

  Discussion Top

DOX is an antineoplastic drug used in the treatment of solid tumors and hematologic malignancies. Despite its wide use, DOX has severe adverse effects; cardiotoxicity is considered to be the most serious [11]. QCT is a type of polyphenolic compound found in many plants, possesses antioxidant, anti-inflammatory, and antiapoptotic actions [5]. There is abundant evidence that oxidative stress plays an essential role in the pathophysiology of DOX-induced cardiotoxicity. Recent study by Chen et al. [12] has explored that coadministering QCT with DOX protects against DOX-induced cardiotoxicity.

In this study, we investigated the protective effects of QCT on DOX-induced cardiotoxicity and the underlying mechanisms of this protection. We found that pretreatment with QCT attenuates DOX-induced oxidative stress, decreases cardiac apoptosis, and tempers DOX-induced cardiotoxicity. These results suggest that QCT could be used as a potential therapeutic tool aiming to prevent DOX-induced cardiotoxicity. These results are in agreement with Kocahan et al. [13] who showed that QCT, a flavonoid compound, ameliorated the toxic effects of DOX and cyclophosphamide on the liver and kidneys induced by oxidative stress through the increase of antioxidant expression and the inhibition of oxidant levels and lipid peroxidation, thus decreasing peroxidative damage.

In this study, DOX administration decreased the final body weight, heart weight, and heart/body weight index of the rats due to their illness. These results are in agreement with Razmaraii et al. [14] who related the decrease in these parameters to DOX toxicity and also with Periyasamy et al. [15] who explained that the decrease in body weight and heart weight in DOX-treated rats may be due to decreased food intake, but these findings were in contrast to Matouk et al. [9] who showed an increase in heart weight and heart/body weight index explained by the hypertrophy and cardiac remodeling due to release of proinflammatory cytokines associated with ROS produced by DOX. Also, Ma et al. [16] found that the heart weight was increased paradoxically by DOX administration due to increased myofibrillar thickness. The wide variation in these findings may be due to the use of different rat strains, different DOX doses, or due to different timings [9],[14],[15],[16]. In addition, this study showed that QCT pretreatment diminished weight loss and improved heart/body weight index compared with the DOX group. These results are in line with the findings of a previous investigator [15].

The development of cardiotoxicity in the DOX group in our study was evidenced by ECG changes in which bradycardia, prolonged QT interval, and elevated ST segment occurred. These results are in agreement with Ma et al. [16]. However, QCT was proved to protect heart from damage as it improved HR and QT intervals. These results are in agreement with Santos et al. [17] who observed that QCT-elicited positive inotropism was dependent on β1-adrenoceptors and was associated with increased intracellular CAMP. Also, Santos et al. [17] showed that the positive cardiac inotropic effect of QCT is related to an increased amplitude of L-type Ca2+ currents.

Troponins are a complex of three protein subunits (troponin C, troponin T, and troponin-I) located on thin filaments of the skeletal and cardiac muscle fibers. Troponin-I is extremely specific for the cardiac muscle and has not been isolated from the skeletal muscle. This absolute specificity makes it an ideal marker of myocardial injury [18].

In this study, the development of cardiotoxicity in the DOX group was also evidenced by elevated serum cTn-I which was in accordance with Atas et al. [19]. However, QCT pretreatment declined serum cTn-I level. This result is in agreement with Yaseen et al. [20]. These findings (ECG improvement and decreasing serum cTn-I level) suggest that QCT protects against DOX-induced cardiotoxicity in rats.

The increased generation of reactive-free radicals from DOX and its metabolite plays an essential role in DOX-induced cardiotoxicity. In comparison with other organs, the heart is especially susceptible to DOX-induced oxidative damage due to the high density of the mitochondria, which are important sources and targets of reactive-free radicals, their increased rate of oxygen consumption and the lower quantity of antioxidant defenses compared with other tissues such as the liver [21]. After DOX enters the cardiomyocytes, it is reduced to the semiquinone form by the effect of mitochondrial enzymes. This reaction results in the generation of high concentrations of ROS like hydrogen peroxide (H2O2) and superoxide anion (O2−) [22]. In addition to producing toxic-free radicals, DOX also decreases endogenous levels of the antioxidant; these effects can induce cardiomyocyte apoptosis [3]. Our results illustrated that serum MDA level was increased as an oxidant and serum TAC was decreased as an antioxidant in the DOX group; these were in agreement with Sun et al. [23]. QCT has been found to have a cardioprotective effect against myocardial infarction, a neuroprotective effect against Alzheimer's disease, a hepatoprotective effect against nonalcoholic steatohepatitis and a chemoprotective effect. These protective effects of QCT have been attributed to its antioxidant activity [24]. In this study, pretreatment with QCT increased TAC acting as an antioxidant and decreased MDA acting as an oxidant; this was in agreement with Dong et al. [25]. These findings suggest that QCT pretreatment protects rat hearts from DOX-induced cardiotoxicity by decreasing oxidative stress and damage.

DOX administration for 2 weeks caused severe histopathological lesions, which were characterized by severe inflammatory cell infiltration, hemorrhage, congested blood vessels, degeneration, and necrosis. These results are in agreement with Iqbal et al. [26]. Additionally, in this study, QCT has anti-inflammatory effect as it improved histopathological features of DOX-induced cardiotoxicity and decreased inflammation, degeneration, and necrosis of myocardium. These results are in agreement with Matouk et al. [9].

Although the mechanisms behind DOX-induced cardiotoxicity have not yet been completely demonstrated, accumulating evidence from previous studies supports cardiac apoptosis considering it as a primary mechanism. It is generally accepted that the oxidative stress aroused by DOX activates apoptotic signals triggering cardiomyocyte apoptosis [27]. For the apoptosis to occur, there are many mediators. Caspase-3 is one of the major contributors to the apoptotic pathway, so it is considered a marker of apoptosis. In this study, we confirmed an increase in apoptosis in DOX-treated rats that was shown in caspase-3 activation detected by IHC staining of cardiac tissue and high apoptotic index in the DOX group; similar results were prenoted by Zhao and Zhang [28]. Moreover, our results have shown that apoptosis was decreased by pretreatment with QCT. These results are in accordance with Chen et al. [29] which support the hypothesis that the protection presented against DOX-induced cardiotoxicity by pretreatment with QCT may involve suppression of cardiac apoptosis.

  Conclusion Top

In conclusion, QCT had cardioprotective effect in DOX-induced cardiotoxicity in rats. This effect could be explained by the decreasing oxidative stress, thereby decreasing apoptosis and subsequent changes to myocardial architecture. Our results suggest that QCT has clinical potential for the treatment of DOX-induced cardiotoxicity. The underlying mechanism responsible for QCT-mediated inhibition of oxidative stress requires further investigation. Future research is also needed to determine whether QCT administration prior to or in combination with treatment with DOX interferes with the antitumor efficacy of DOX.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]

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