Entry #: 35
Date: 27 January 2018
Section: Phenolic compounds
Topic: Oleuropein and doxorubicin cardiomyopathy
Type: In vivo model
OliveNetTM Journal Club
Expert review of literature related to olives and olive oil
D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis
Oleuropein revents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism
Andreadou et al
Citation / Year
(1) / 2014
Olive phenolic, oleuropein, doxorubicin, cardiotoxicity, cardiomyopathy, left ventricular contractility, inflammation
Doxorubucin is a frontline anthracycline chemotherapeutic which is associated with inducing oxidative-stress and cardiotoxicity (2). Indeed, in the clinic doxorubicin-induced cardiomyopathy is dose-limiting, and people that develop anthracycline-induced cardiomyopathy have a poor prognosis (3). Antioxidants, including numerous dietary antioxidants, such as oleuropein, have been utilised to protect from doxorubicin-induced cardiotoxicity (4, 5). However, most of the studies both in cell culture and in vivo have focussed on acute (short-term) models. The aim of this study was to investigate the ability of the major olive phenolic, oleuropein to protect from doxorubicin-induced cardiomyopathy in a chronic animal model of doxorubicin-induced cardiomyopathy. As series of detailed histological and molecular biological techniques were utilised to elucidate a cellular and molecular mechanisms of action.
Key points and implications
Firstly, a cell culture experiment using the PC-3 human prostate cancer cell line, indicated dose-dependent inhibition of cell growth with 3-100 nM doxorubicin over a 96 hour period. Oleuropein alone at 3-100 μg/mL did not significantly reduce the viability of PC-3 cells, and combinations of oleuropein with doxorubicin did not exhibit reductions in viability compared to doxorubicin alone. For the in vivo study, at total of 90 male Wistar rats were divided into six groups as follows: 1) control (n = 15, intraperitoneal [i.p.] injection of 2 mL saline for two weeks), 2) oleuropein group 1 (n=6, i.p. injection of 1000 mg/Kg oleuropein in equal doses over two weeks, 3) oleuropein group 2 (n=6, i.p. injection of 2000 mg/Kg oleuropein in equal doses over two weeks), 4) doxorubicin group (n=21, i.p. injection of 18 mg/Kg in six equal doses over two weeks, 5) oleuropein 1 and doxorubicin (n=21), and 6) oleuropein 2 and doxorubicin (n=21). Oleuropein was administered on odd days and doxorubicin on even days. In summary, the findings from echocardiography, histological, and molecular biological analyses indicated: 1) impaired left ventricular contractility in the doxorubicin group compared to other groups, 2) inflammation in the doxorubicin group, 3) degenerative pathological lesions (edema, vacuolisation) in the doxorubicin group, 4) higher levels and activation of the molecular markers, MDA, PCs, NT, IL-6, Big ET-1, iNOS, Akt and AMPK were observed in the doxorubicin group, 5) lower levels of eNos in the doxorubicin group, and 6) significant changes in metabolic profile indicating altered energy metabolism and protein biosynthesis in the doxorubicin group. On the basis of their findings, the authors have elegantly highlighted the effect of oleuropein on doxorubicin-induced cardiotoxicity at the molecular level, in the final figure of the manuscript (1). Overall, they highlight that oleuropein has pleiotropic effects in key molecular pathways including those associated with cardiac contractility, nitro-oxidative stress, energy metabolism, and cellular signalling pathways associated with cell growth and apoptosis (1). These are very interesting findings and provide the basis for further preclinical evaluation, with a view to ultimate investigation in clinical trials.
- I. Andreadou et al., Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. Journal of molecular and cellular cardiology 69, 4-16 (2014).
- K. Renu, G. A. V, B. T. P, S. Arunachalam, Molecular mechanism of doxorubicin-induced cardiomyopathy – An update. European journal of pharmacology 818, 241-253 (2018).
- G. M. Felker et al., Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. The New England journal of medicine 342, 1077-1084 (2000).
- I. Andreadou et al., The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits. The Journal of nutrition 136, 2213-2219 (2006).
- I. Andreadou et al., Acute doxorubicin cardiotoxicity is successfully treated with the phytochemical oleuropein through suppression of oxidative and nitrosative stress. Journal of molecular and cellular cardiology 42, 549-558 (2007).