Grape seed proanthocyanidins ameliorate Doxorubicin-induced cardiotoxicity.
Doxorubicin (Dox) is one of the most widely used and successful chemotherapeutic antitumor drugs. Its clinical application is highly limited due to its cumulative dose-related cardiotoxicity. Proposed mechanisms include the generation of reactive oxygen species (ROS)-mediated oxidative stress. Therefore, reducing oxidative stress should be protective against Dox-induced cardiotoxicity. To determine whether antioxidant, grape seed proanthocyanidin extract (GSPE) attenuates Dox-induced ROS generation and protects cardiomyocytes from Dox-induced oxidant injury, cultured primary cardiomyocytes were treated with doxorubicin (Dox, 10 microM) alone or GSPE (50 microg/ml) with Dox (10 microM) for 24 hours. Dox increased intracellular ROS production as measured by 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, induced significant cell death as assessed by propidium iodide, and declined the redox ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) and disrupted mitochondrial membrane potential as determined by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethlbenzimidazole-carbocyanide iodine (JC-1). Analysis of agarose gel electrophoresis revealed Dox-induced nuclear DNA damage with the ladder like fragmentation. GSPE treatment suppressed those alterations. Electron Spin Resonance (ESR) spectroscopy data also showed that GSPE strongly scavenged hydroxyl radical, superoxide and DPPH radicals. Together, these findings indicate that GSPE in combination with Dox has protective effect against Dox-induced toxicity in cardiomyocytes, which may be in part attributed to its antioxidative activity. Importantly, flow cytometric analysis demonstrated that co-treatment of Dox and GSPE did not decrease the proliferation-inhibitory effect of Dox in MCF-7 human breast carcinoma cells. Thus, GSPE may be a promising adjuvant to prevent cardiotoxicity without interfering with antineoplastic activity during chemotherapeutic treatment with Dox.
Li
Jing
J
Emergency Resuscitation Center, Department of Medicine, University of Chicago, IL 60637, USA.
Liu
Huiping
H
Ramachandran
Srinivasan
S
Waypa
Gregory B
GB
Yin
Jun-Jie
JJ
Li
Chang-Qing
CQ
Han
Mei
M
Huang
Hsien-Hao
HH
Sillard
Willard W
WW
Vanden Hoek
Terry L
TL
Shao
Zuo-Hui
ZH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D056604:Grape Seed Extract / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D044945:Proanthocyanidins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D016166:Free Radical Scavengers; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D005978:Glutathione; D019803:Glutathione Disulfide