Atividade protetora da diosmina sobre a cardiotoxicidade induzida pela doxorrubicina em camundongos com sarcoma 180

Abstract

Protective activity of Diosmin on doxorubicin-induced cardiotoxicity in mice with Sarcoma 180. Sara Albuquerque dos Santos, São Cristovão, 2022. Introduction: Cancer is a serious pathology in the context of public health with high mortality rates. Doxorubicin (Dox) is an antineoplastic used in the treatment of the disease and generates dose-dependent cardiotoxicity caused by oxidative stress, inflammation and apoptosis. Diosmin (Dios), a natural product with an antioxidant, anti-inflammatory and anti-apoptotic effect, shows promise for protecting the cardiac toxic effects caused by Dox. Objective: In this study, the protective activity of Diosmin on doxorubicin-induced cardiotoxicity in mice with Sarcoma 180 (S180) was investigated. Methods: Diosmin interference on cell proliferation was evaluated through in vitro cytotoxicity in 6 cell lines: human breast carcinoma (MCF-7), human colon carcinoma (HCT116), human hepatocellular carcinoma (HepG2), human promyelocytic leukemia (HL-60), human lung fibroblast (MRC-5) and Sarcoma 180 (S180). To evaluate the antitumor activity in vivo, 70 mice were divided into 7 groups: Saline (0.9% p.o.), Positive Control (Cyclophosphamide, 15 mg/kg/day p.o.), Dox alone (2 mg/kg/day i.p.), Dios 50 (50 mg /kg/day p.o.), Dios 100 (100 mg/kg/day p.o.), Dox + Dios 50 (2 mg/kg/day i.p. + 50 mg/kg/day p.o) and Dox + Dios 100 (2 mg/kg/day i.p. + 100 mg/kg/day p.o.), with a 7-day treatment. To assess cardiotoxicity, 50 mice were divided into 5 groups: Saline (0.9% p.o.), Dox (2 mg/kg/day i.p.), S180 + Dox (Dox 2 mg/kg/day i.p.), S180 + Dox + Dios 50 (2 mg/kg/day i.p. + 50 mg/kg/day p.o.) and S180 + Dox + Dios 100 (2 mg/kg/day i.p. + 100 mg/kg/day p.o.) with 9 days treatment. After 24 hours, electrocardiographic evaluation, blood collection and organ removal were performed. Toxicological aspects were evaluated and the antioxidant effect of Diosmin was measured. Finally, the histomorphological analysis of the hearts and tumors was performed. Results: Diosmin showed no inhibition of cell proliferation for any of the 6 cell lines, on the other hand, Dox showed cytotoxic activity for all cell lines. Regarding in vivo antitumor activity, the Dios groups at doses of 50 and 100 mg/kg/day associated with Dox (2 mg/kg/day) when compared to the saline group showed a significant reduction in tumor growth (inhibition of 48.8 % and 43.4%, respectively). However, when compared to the Dox (2 mg/kg/day) group alone, there was no statistically significant difference (p > 0.05). These results showed that Diosmin at the doses tested did not interfere with the antitumor activity of Dox against the S180 model. The evaluation of the electrocardiographic recordings showed that the groups treated with Dox (with and without S180) showed significant variations (p<0.05) in the ECG in relation to the PRi and QTc intervals and the Heart Rate (HR) when compared to the saline group. Diosmin, however, recovered the PRi, QTc and HR intervals. In addition, regarding toxicological aspects, Diosmin preserved cardiac mass, reduced cardiac injury markers (AST, CK-MB, LDH) and at a dose of 100 mg/kg/day, recovered the leukocyte pattern. When evaluating the antioxidant effect, Diosmin protected the heart against lipid peroxidation and restored the activity of endogenous antioxidant enzymes. Histologically, Diosmin promoted a noticeable reduction in the areas of morphological alterations such as hydropic vacuolar degeneration, expressed by “ballooned” morphology, induced by Dox. Conclusion: This study demonstrated that Diosmin recovered electrocardiographic patterns, minimized toxicological effects, reestablished antioxidant activity and preserved cardiac morphohistological architecture, without interfering with the antitumor activity of Dox.