TY - JOUR
T1 - Grape seed proanthocyanidins ameliorate doxorubicin-induced cardiotoxicity
AU - Li, Jing
AU - Liu, Huiping
AU - Ramachandran, Srinivasan
AU - Waypa, Gregory B.
AU - Yin, Jun Jie
AU - Li, Chang Qing
AU - Han, Mei
AU - Huang, Hsien Hao
AU - Sillard, Willard W.
AU - Vanden Hoek, Terry L.
AU - Shao, Zuo Hui
N1 - Funding Information:
This work was supported by the NIH grants AT01575, AT003441 and MURI (Multi-University Research Initiative) award N00014-04-1-0796 from the US, Department of Defense Office of Naval Research. The authors thank Prof. C.S. Yuan (Tang Center for Herbal Medicine Research, University of Chicago) for his generous gift of GSPE and Prof. B. Kalyanaraman (Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin) for his generous gift of BMPO.
PY - 2010
Y1 - 2010
N2 - 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 μM) alone or GSPE (50 μg/ml) with Dox (10 μM) 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.
AB - 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 μM) alone or GSPE (50 μg/ml) with Dox (10 μM) 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.
KW - Cardiomyocyte
KW - Cardiotoxicity
KW - Doxorubicin
KW - Grape seed proanthocyanidin extract
KW - Reactive oxygen species
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U2 - 10.1142/S0192415X10008068
DO - 10.1142/S0192415X10008068
M3 - Article
C2 - 20503473
AN - SCOPUS:77953549260
VL - 38
SP - 569
EP - 584
JO - Comparative Medicine East and West
JF - Comparative Medicine East and West
SN - 0192-415X
IS - 3
ER -