Atividade anti-inflamatória e cardioprotetora do alfa-bisabolol sobre a cardiotoxicidade induzida por doxorrubicina em camundongos C57BL/6

Abstract

Introduction: Cardiotoxicity is a side effect resulting from the treatment of cancer patients with anthracyclines. Doxorubicin is one of the most frequently drugs used for the management of several types of cancer in adults and pediatrics, including breast cancer, the most prevalent in women. Unfortunately, despite its effectiveness, the clinical significance of incorporating doxorubicin in cancer therapy is undermined by its toxicities. It is which usually manifested as cardiotoxicity up to years after discontinuation of treatment. It is then especially important in cardio-oncology research to identify therapies to delay or prevent the occurrence of doxorubicin-related cardiovascular complications. Alpha-bisabolol is a sesquiterpene alcohol with an important anti-inflammatory action described. The present study aimed to investigate the role of alpha-bisabolol on doxorubicin-induced cardiotoxicity. Methods: C57BL/6 male mice (25-25g) were divided into groups (n=6/group) and injected with 0.9% saline (6 ml/kg + 2% tween 20 2% i.p 1xday/19 days, i.p.), doxorubicin (4 mg/kg on days 0, 7, and

14, i.p.) alone or 1 h before alpha-bisabolol (50 mg/kg, once daily/19 days, p.o.) or alpha- bisabolol alone for 19 days. Body mass change was assessed daily. On day 20,

electrocardiographic (ECG) parameters were evaluated and a blood sample was obtained for biochemical analysis. After euthanasia, heart samples were extracted for histopathology and measuring inflammatory markers. Results: Doxorubicin induced a significant loss of body and cardiac masses, histopathological alterations characterized by the reduction of the cardiomyocyte area, parameters partially attenuated by the treatment with alpha-bisabolol (p<0.05 vs. doxorubicin group). Additionally, these alterations were accompanied by alterations in the ECG causing prolongation of the ST, QRS, and QTc waves, together with a decrease in the T wave, alterations that were prevented by alpha-bisabolol. Besides, doxorubicin increased serum levels of creatine phosphokinase MB fraction (CK-BM), which was associated with cardiomyocyte injury and death and neutrophilic infiltrate. Inflammation response was marked by increased expression of neutrophils in cardiac tissue, accompanied by increased expression of Toll like receptors (TLR9) and phosphoinositide 3 kinase gamma (PI3K-gamma), culminating with the production of cytokines (IL-1beta, IL-6 and IL-10). All these parameters were significantly attenuated by alpha-bisabolol treatment (p<0.05 vs. doxorubicin group). Conclusion: Alpha-bisabolol demonstrated an anti-inflammatory activity, attenuating the development of doxorubicin-associated cardiotoxicity.