Carnosic acid mitigates doxorubicin-induced cardiac toxicity: Evidence from animal and cell model investigations

Abstract

Objectives: Utilization of doxorubicin (DOX) as a chemotherapy medication is limited due to its cardiotoxic effects. Carnosic acid exerts antioxidant, anti-inflammatory, besides cytoprotective effects. The objective of this study was to investigate the ability of carnosic acid to protect rat hearts and the MCF7 cell line against cardiotoxicity induced by DOX.

Materials and methods: The study involved the classification of male Wistar rats into seven groups: 1) Control 2) DOX (2 mg/kg, every 48h, IP, 12d), 3-5) Carnosic acid (10, 20, 40 mg/kg/day, IP, 16d)+ DOX, 6) Vitamin E (200 mg/kg, every 48h, IP, 16d)+ DOX 7) Carnosic acid (40 mg/kg/day, IP, 16d). Finally, cardiac histopathological alterations, ECG factors, carotid blood pressure, left ventricular function, heart-to-body weight ratio, oxidative (MDA, GSH), inflammatory (IL-1β, TNF-α), plus apoptosis (caspase 3, 8, 9, Bcl-2, Bax) markers were evaluated. DOX toxicity and carnosic acid ameliorative effect were evaluated on MCF7 cells using the MTT assay.

Results: DOX augmented the QRS duration, QA, RRI, STI, and heart-to-body weight ratio, and reduced HR, LVDP, Min dP/dt, Max dP/dt, blood pressure, boosted MDA, TNF-α, IL1-β, caspase 3,8,9, Bax/Bcl-2 ratio, decreased GSH content, caused fibrosis, necrosis, and cytoplasmic vacuolization in cardiac tissue but carnosic acid administration reduced the toxic effects of DOX. The cytotoxic effects of DOX were not affected by carnosic acid at concentrations of 5 and 10 μM.

Conclusion: Carnosic acid as an anti-inflammatory and antioxidant substance is effective in reducing DOX-induced damage by enhancing antioxidant defense and modifying inflammatory signal pathway activity and can be used as an adjunct in treating DOX cardiotoxicity.

Keywords: Anti-Inflammatory agents; Anti-oxidants; Cardiotoxicity; Electrocardiography; Salvin; Vitamin E.

Figure 1

Effect of carnosic acid on doxorubicin induced histopathological changes in the heart tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups

Figure 2

Effect of carnosic acid and doxorubicin on A) Collagen deposition, B) myocardial necrosis, and C) Cytoplasmic vacuolization in cardiac tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups (on a scale of 1 to 4, with 1 signifying normal and 4 indicating the most serious harm)

Figure 3

Effect of carnosic acid on A) lipid peroxidation and B) GSH reduction induced by DOX in the heart tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups

Figure 4

Effect of carnosic acid on the Bax/Bcl-2 ratio and pro and cleaved-caspase3 levels in the heart tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups

Figure 5

Effect of carnosic acid on pro and cleaved-caspase8 and caspase-9 levels in the heart tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups

Figure 6

Effect of carnosic acid on IL-1β and TNF-α levels in the heart tissue of control, doxorubicin, carnosic acid, and vitamin E treated groups

Figure 7

Effect of 1-10 μM doxorubicin (DOX) concentrations on MCF7 cells for 24 hr

Figure 8

Effect of 5-100 μM carnosic acid concentrations on the viability

Figure 9

Effect of 5 and 10 μM carnosic acid concentrations on the viability