Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism

Andreadou, Ioanna; Mikros, Emmanuel; Ioannidis, Konstantinos; Sigala, Fragiska; Naka, Katerina K.; Kostidis, Sarantos; Farmakis, Dimitrios; Τέντα, Ρωξάνη; Kavantzas, Nikolaos; Bibli, Sofia-Iris; Gikas, Evagelos; Skaltsounis, Léandros; Kremastinos, Dimitrios Th.; Iliodromitis, Efstathios K.

doi:10.1016/j.yjmcc.2014.01.007

Cited by 101 publications

(85 citation statements)

References 63 publications

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“…A similar mechanism was also observed in breast cancer cells (12). Additionally, a recent study on cardiomyopathy demonstrated that oleuropein has a protective effect in doxorubicin-induced cardiomyopathy through the activation of AMPK and suppression of iNOS (11). In the current study, evidence is presented for a role of oleuropein as an inhibitor of cell growth and an inducer of apoptosis, which suggests that oleuropein possesses antitumor activity in HCC.…”

Section: Discussionsupporting

confidence: 78%

“…The primary component of olive leaf extract is oleuropein. Andreadou et al reported that oleuropein is involved in cardiomyocyte metabolism through the activation of AMP-activated protein kinase α (AMPK) and suppression of inducible nitric oxide synthases (iNOS) (11). It has recently been reported that oleuropein may have therapeutic potential in a number of types of cancer, including breast cancer (12), thyroid cancer (13) and colorectal cancer (14), via inhibition of cell growth induction of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line

Yan

Chai

Cai

et al. 2015

Molecular Medicine Reports

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Abstract.Oleuropein is a polyphenol, that is found in extra-virgin olive oil. Previous studies have shown that oleuropein inhibits cell proliferation and induces apoptosis in breast cancer, colorectal cancer and thyroid cancer. The aim of the present study was to investigate the effects of oleuropein in hepatocellular carcinoma (HCC) cells. The results of Cell Counting Kit 8 and flow cytometric analysis indicated that oleuropein effectively inhibited cell viability and induced apoptosis in HepG2 human hepatoma cells in a dose-dependent manner, through activation of the caspase pathway. Proapoptotic Bcl-2 family members, BAX and Bcl-2, were involved in oleuropein-induced apoptosis. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway was also shown to be involved in this process. Oleuropein was demonstrated to suppress the expression of activated AKT. In addition, AKT overexpression promoted cell survival following treatment with oleuropein, while inhibition of AKT promoted cell death. Furthermore, the data demonstrated that oleuropein induces the production of reactive oxygen species (ROS) and that the function of oleuropein is, at least partially, ROS-dependent. These results suggest that oleuropein may be a promising novel chemotherapeutic agent in hepatocellular carcinoma. IntroductionHepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality (1). The predominant risk factors for HCC development are infection with hepatitis B or C virus, obesity and excess alcohol intake. The incidence and mortality of HCC is increasing as a result of the current obesity epidemic and rise in alcohol consumption (2). However, only 10-20% of patients with HCC are eligible for surgical resection, due to poorly preserved liver function, portal vein invasion or extrahepatic spread. Furthermore, the risk of recurrence following HCC resection is high (3,4). The available chemotherapeutic and radiotherapeutic treatment options for patients with advanced HCC are also extremely limited. Therefore, it is necessary to develop effective and practical chemotherapeutic agents with minimal cytotoxicity for use in this disease.A number of previous studies have shown that regular consumption of coffee, vitamin E and fish oil may be associated with a reduced risk of developing HCC (5-7). Ecological studies have investigated the association between dietary fat and certain types of cancer (8,9). Hursting et al (8) demonstrated that the intake of saturated or polyunsaturated fats was associated with incidence of breast and prostate cancer. A causal relationship was identified between cholesterol intake and colon cancer (9). Olive oil is the oil obtained from the fruit of the olive tree (Olea europaea Sativa) and its consumption is associated with lower overall mortality patterns, which are observed in Mediterranean populations (10). The primary component of olive leaf extract is oleuropein. Andreadou et al reported that oleuropein is involved in cardiomyocyte metabolism through the activati...

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line

Yan

Chai

Cai

et al. 2015

Molecular Medicine Reports

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“…Similar biochemical changes have been seen in several other studies (Fouad et al, 2013;Andreadou et al, 2014;Saeed et al, 2015). The elevated levels of MDA and NO, due to the doxorubicin-induced toxicity, were significantly impeded by AcoA treatment.…”

Section: Discussionsupporting

confidence: 87%

The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice

Ezzat

Gaafary

Sayed

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The current study aimed to investigate the protective effect of the cardenolide glycoside acovenoside A (AcoA) against doxorubicininduced cardiotoxicity in mice. AcoA was isolated from the pericarps of Acokanthera oppositifolia to chemical homogeneity and characterized by means of one-and two-dimensional nuclear magnetic resonance spectroscopy. AcoA exhibited relatively low toxicity in mice (LD 50 5 223.3 mg/kg bw). Repeated administration of doxorubicin induced cardiotoxicity manifested by reduced activity of myocardial membrane-bound ion pumps and elevated serum biomarkers of myocardial dysfunction, oxidative stress, and inflammation. Pretreatment of doxorubicin-exposed mice with AcoA (11.16 or 22.33 mg/kg bw, i.p.) for 2 weeks after 2 weeks of combined administration of AcoA and doxorubicin protected the animals dose dependently against doxorubicininduced cardiotoxicity as indicated by normalization of the levels of different myocardial markers of oxidative stress (malondialdehyde, nitric oxide, total antioxidant capacity, and cardiac glutathione), serum myocardial diagnostic marker enzymes (serum cardiac troponin T, creatine kinase isoenzyme MB, aspartate aminotransferase, and lactate dehydrogenase), and inflammatory markers (c-reactive protein, tumor necrosis factor-a, and interleukin-6), as well as myocardial Na 1 /K 1 -ATPase activity. These effects were attributed to the negative impact of AcoA on transcription factors nuclear factor kB and interferon regulatory factor 3/7. Thus acovenoside A might act as a cardioprotective agent to prevent doxorubicin-induced cardiotoxicity.

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“…Our findings show that oleuropein reduces proinflammatory cytokines and increased antioxidant markers. Such findings are similar to those that reported that oleuropein reduced prooxidants and proinflammatory cytokines and increased antioxidant markers in adriamycin cardiotoxicity (Andreadou et al 2014;Andreadou et al 2007) and myocardial ischemia/reperfusion (Andreadou et al 2006;Manna et al 2004) studies.…”

Section: Discussionsupporting

confidence: 91%

“…Such a conclusion receives support from previous studies demonstrating that oleuropein was cardioprotective against acute and chronic doxorubicin-induced cardiotoxicities (Andreadou et al 2014;Andreadou et al 2007) and ischemia-reperfusion injuries (Andreadou et al 2006). The cardioprotective effects of oleuropein have been attributed to several mechanisms such as reduction of oxidative and nitrosative stress (Andreadou et al 2007) as well as antiplatelet (Petroni et al 1995), hypolipidemic (Andreadou et al 2006), and antiinflammatory (Andreadou et al 2014) activities. We, therefore, sought to measure serum levels of SOD, GRx, MDA, IL-1β, and TNF-α to examine the role of oxidative stress and proinflammatory cytokines in the oleuropein's cardioprotective effects.…”

Section: Discussionsupporting

confidence: 53%

Oleuropein attenuates the progression of heart failure in rats by antioxidant and antiinflammatory effects

Janahmadi

Nekooeian

Moaref

et al. 2016

Naunyn-Schmiedeberg's Arch Pharmacol

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Much of the beneficial effects of olive products have been attributed to oleuropein. This study examined the effects of oleuropein in rats with heart failure induced by permanent ligation of left coronary arteries. Twenty-four hours after the operation, the rats were assigned to five groups including a sham assigned to receive vehicle (1 ml/day) and four coronary ligated groups assigned to receive vehicle or oleuropein at 5, 10, or 20 mg/kg/day. Five weeks later, echocardiographic and hemodynamic parameters, serum concentrations of oxidative stress, and inflammatory markers were determined. Myocardial infarction group receiving vehicle showed impaired hemodynamic and echocardiographic parameters as evidenced by decreased left ventricular systolic pressure, rate of rise and decrease of left ventricular pressure, stroke volume, ejection fraction, and cardiac output. In addition, significant reduction in superoxide dismutase and glutathione reductase was observed. Oleuropein treatment prevented the reduction of these variables. Moreover, the group had a significantly higher infarct size and serum malondialdehyde, interleukin-1β, and tumor necrosis factor-α than those of the sham group. Treatment with oleuropein prevented the increase of these variables. The results show that oleuropein attenuates the progression of heart failure, possibly by antioxidative and antiinflammatory effects.

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Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism

Cited by 101 publications

References 63 publications

Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line

Oleuropein induces apoptosis via activation of caspases and suppression of phosphatidylinositol 3-kinase/protein kinase B pathway in HepG2 human hepatoma cell line

The Cardenolide Glycoside Acovenoside A Affords Protective Activity in Doxorubicin-Induced Cardiotoxicity in Mice

Oleuropein attenuates the progression of heart failure in rats by antioxidant and antiinflammatory effects

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