Procyanidins Produce Significant Attenuation of Doxorubicin‐Induced Cardiotoxicity via Suppression of Oxidative Stress

Abstract

Doxorubicin is widely prescribed in the chemotherapy of haematological malignancies and solid tumours. The major side effect of doxorubicin is oxidative injury-related cardiotoxicity, which has dramatically hindered its usage. Procyanidins from grape seeds are potent free radical scavengers that have been shown to protect against anthracyclineinduced cardiotoxicity. In the present study, we tested whether procyanidins would prevent the doxorubicin-induced cardiotoxicity in rats. Rats were intraperitoneally treated with doxorubicin at a cumulative dose of 15 mg/kg with and without pre-administration of procyanidins. Our data showed that doxorubicin led to cardiac function deterioration, myocardial injury and increased oxidative stress in cardiac tissues. The cardiac function deterioration by doxorubicin included increased QT-interval and ST-interval in electrocardiograph (ECG) and decreased left ventricular developed pressure. Doxorubicininduced myocardial injury was shown by the increased creatine kinase, alanine aminotransferase and aspartate aminotransferase in serum as well as in myocardial lesions. Pretreatment with procyanidin (150 mg/kg daily) effectively hindered the adverse effects of doxorubicin, such as myocardial injury and impaired heart function. Procyanidin pretreatment attenuated cytoplasmic vacuolization, increased left ventricular developed pressure and improved the ECG. The cardioprotective effect of procyanidin corresponded to the decrease of lipid peroxidation and the increase of cardiac antioxidant potency in doxorubicintreated rats that were also given procyanidin. An in vitro cytotoxic study showed that procyanidins did not attenuate the antineoplastic activity of doxorubicin to A549 adenocarcinoma cells. All the above lines of evidence suggest that procyanidins protect cardiomyocytes from doxorubicin-induced cardiotoxicity via suppression of oxidative stress.

Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats

“…17,18,[25][26][27] Alterations in physiological parameters are well known as one of the toxic effects of DOX, which is characterized by reduced body and heart weights. [28][29][30] Our findings here confirmed the literature reports that DOX treatment leads to decreased both body and heart weights in animals 31 and that GSE treatment increased body and heart weights, as compared to DOX group. Our data supported previous findings in which DOX administration significantly resulted in increased left ventricular dysfunction and decreased the FS and EF in the echocardiographic assessment.…”

“…50 In addition, it was reported that procyanidin, an antioxidant flavonoid of the GSE, exhibited antitumor activity on MCF7 cells. In this regard, other studies have demonstrated that procyanidins induce cytotoxicity on several tumor cells such as human adenocarcinoma cells A549, 31 human colorectal cancer HT29, LoVo cells, 51 A-427 human lung cancer cells, CRL-1739 human gastric adenocarcinoma cells and K562 chronic myelogenous leukemic cells. 52 During the two past decades tremendous effort has been put into uncovering the molecular mechanisms and/or intracellular targets involved in the DOX-induced cardiotoxicity and different hypotheses have been developed to explain this phenomenon, [53][54][55] but no single one of these was able to fully explain it.…”

“…Our data confirmed previous findings suggesting GSE attenuated the detrimental impacts of DOX on morphology and ultrastructure of heart tissues in histopathology studies. 27,31 Furthermore, the results of the MTT assay indicated that DOX exerts a dose-dependent cytotoxic effect on MCF7 cells and that GSE treatment in combination with DOX had no significant effect on DOX-induced cell toxicity and GSE alone showed cytotoxicity effect on MCF7 cells. 50 In addition, it was reported that procyanidin, an antioxidant flavonoid of the GSE, exhibited antitumor activity on MCF7 cells.…”

Grape Seed Proanthocyanidins Extract Prevents Cisplatin-induced Cardiotoxicity in Rats

“…It has been reported that GSPE conferred cardio protection against exogenous H 2 O 2 _ and antimycin A-induced oxidant injury by reactive oxygen species scavenging and iron chelating (Shao et al 2003). More reports stated that procyanidins could play a part in the cardiac protective effect by suppressing of oxidative stress (Li et al 2009). …”

The Protective Effect of Grape Seed Extract on Cardiotoxicity Induced by Doxorubicin Drug in Male Rats

“…ROS generated during cancer chemotherapy may also decrease the efficacy of the treatment by interfering with drug induced apoptosis and cell cycle progression, which are optimal effect on cancer cells [6] [7]. Doxorubicin (DOX) is one of the most widely used and successful chemotherapeutic anti-tumour drugs prescribed in hematological malignancies and solid tumors [8]. Its clinical application is limited due to its cumulative dose-related cell toxicity.…”