Myricetin (3,3',4',5,5',7-Hexahydroxyflavone) Prevents 5-Fluorouracil-Induced Cardiotoxicity

Abstract

5-Fluorouracil (5-FU) is a strong anti-cancer drug used to manage numerous cancers. Cardiotoxicity, renal toxicity, and liver toxicity are some of the adverse effects which confine its clinical use to some extent. 5-FU-induced organ injuries are associated with redox imbalance, inflammation, and damage to heart functioning, particularly in the present study. Myricetin is an abundant flavonoid, commonly extracted from berries and herbs having anti-oxidative and anti-cancer activities. We planned the current work to explore the beneficial effects of myricetin against 5-FU-induced cardiac injury in Wistar rats through a biochemical and histological approach. Prophylactic myricetin treatment at two doses (25 and 50 mg/kg) was given to rats orally for 21 days against cardiac injury induced by a single injection of 5-FU (150 mg/kg b.wt.) given on the 20th day intraperitoneally. The 5-FU injection induced oxidative stress, inflammation, and extensive cardiac damage. Nevertheless, myricetin alleviated markers of inflammation, apoptosis, cardiac toxicity, oxidative stress, and upregulated anti-oxidative machinery. The histology of heart further supports our biochemical findings mitigated by the prophylactic treatment of myricetin. Henceforth, myricetin mitigates 5-FU-induced cardiac damage by modulating oxidative stress, inflammation, and cardiac-specific markers, as found in the present study.

Figure 1

Structure of myricetin.

Figure 2

(A,B) Effect of myricetin treatment on QR and XO in 5-FU-induced cardiotoxicity in Wistar rats. (A) The level of XO was found to be significantly elevated (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment significantly reduced the XO level in group III (#p < 0.05) and group IV (##p < 0.01) compared to that in group II. (B) Significantly depleted levels of QR (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment significantly restored the QR level in both the groups (#p < 0.05 and ##p < 0.01). The data obtained was presented as mean ± SD (n = 6).

Figure 3

(A,B) Effect of myricetin on MPO and NO levels in 5-FU-induced cardiac damage. (A) The level of MPO was found to be significantly elevated (***p < 0.001) in 5-FU-treated group II in comparison to that in the control group (group I). However, both the doses of myricetin treatment markedly reduced the MPO levels in the respective groups (##p < 0.01 and ###p < 0.001). (B) The level of NO was also found to be significantly elevated (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment markedly reduced the NO level in group III (#p < 0.05) and group IV (##p < 0.01) compared to that in group II.

Figure 4

(A–D) Effect of myricetin on cardiotoxicity markers (LDH, MCP, CK-MB, and cTn-1) in 5-FU-induced cardiac damage. (A) Significantly elevated levels of LDH were observed (***p < 0.001) in 5-FU-treated group II in comparison to that in the control group (group I). Treatment with myricetin markedly reduced the LDH levels in the respective groups (#p < 0.05 and ###p < 0.01). (B) The level of MCP was also found to be significantly elevated (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment markedly reduced the MCP levels in group III (#p < 0.05) and group IV (##p < 0.01) compared to that in group II. (C) The level of another cardiotoxicity marker CK-MB was found to be significantly elevated (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment significantly reduced the CK-MB levels in group III (##p < 0.01) and group IV (###p < 0.001) compared to that in group II. (D) Another important marker cardiac troponin cTn-1 showed a steep increase after treatment in the 5-FU-treated group (group II). Myricetin treatment was successful in bringing down the elevated levels of cTn-1 at both the doses analyzed (##p < 0.01 and ###p < 0.001).

Figure 5

(A,B) Effect of myricetin on apoptotic marker proteins (BAX and caspase-3) in 5-FU-induced cardiac damage. (A) The level of BAX was found to be significantly elevated (***p < 0.001) in 5-FU-treated group II in comparison to that in the control group (group I). However, both the doses of myricetin treatment markedly reduced the BAX levels in the respective groups (#p < 0.05 and ###p < 0.001). (B) The level of caspase-3 was also found to be significantly elevated (***p < 0.001) in group II treated with 5-FU in comparison to that in the control group (group I). However, myricetin treatment markedly reduced the caspase-3 level in group III (##p < 0.01) and group IV (###p < 0.001) compared to that in group II.

Figure 6

Microphotograph of hematoxylin and eosin-stained sections of heart 5-FU-treated group (group II) showed many pathological indications such as necrosis, infiltration, nuclear condensation, and necrosis of cardiomyocytes, group III showed mild degree of cardiac damage and inflammatory cell, and group IV showing almost normal appearance of cardiac histoarchitecture.