© 2007 The Authors
© 2007 Nordic Pharmacological Society
. Basic & Clinical Pharmacology & Toxicology
Blackwell Publishing Ltd
: A Novel Adjunct to Prevent Doxorubicin-Induced
*, Guo-Liang Zhou
*, Min Shen
*, Yun-Xiang Chen
and Yao-Xian Xuan
, Shu-Peng Liu
, Guo-Chan Chen
, Hao Chen
, Zhen-Qiang You
State Key Laboratory of Safety Evaluation for New Drugs, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang, China, and
Institutes of Biomedical Engineering, Shanghai University, Shanghai, China
(Received April 23, 2007; Accepted June 12, 2007)
tumours, but its use is limited by formation of metabolites that induce acute and chronic cardiac toxicities.
has been widely used to treat cardiovascular and cerebrovascular diseases in China. In the present study, we used an
mouse model to explore whether
could protect against doxorubicin-induced chronic cardiotoxicity. Male ICR
mice were treated with distilled water or water extraction of
or doxorubicin (15 mg/kg, intravenously) treatments weekly. Cardiotoxicity was assessed by electrocardiograph, antioxidant
activity in cardiac tissues, serum levels of creatine kinase, aspartate aminotransferase (AST) and histopathological change
in cardiac tissues. A cumulative dose of doxorubicin (60 mg/kg) caused animal death and myocardial injury characterized
by increased QT interval and decreased heart rate in electrocardiograph, decrease of heart antioxidant activity, increase of
serum AST, as well as myocardial lesions. Pre-treatment with
performance of the doxorubicin-treated mice as evidenced from normalization of antioxidative activity and serum AST,
preventing loss of myofibrils as well as improving arrhythmias and conduction abnormalities. Furthermore, the
cytotoxic study showed that
did not compromise the antitumour activity of doxorubicin. These results suggested
elicited a typical cardioprotective effect on doxorubicin-related oxidative stress, and could be a novel
adjunct in the combination with doxorubicin chemotherapy.
: Doxorubicin is an anthracycline antibiotic agent used in the treatment of a variety of solid and haematopoietic
(15 g/kg, orally) daily for 4 weeks, followed by saline
significantly reduced mortality and improved heart
Doxorubicin, an anthracyclin antibiotic, is primarily used in
the treatment of haematological malignancies as well as solid
tumours, exerting its effect by intercalating into DNA .
However, cardiotoxicity induced by doxorubicin is one of the
most serious side effects that greatly limits its use . The
mechanisms for doxorubicin-induced cardiotoxicity includes
generation of free oxygen radicals, expression of nitric oxide
synthase, changes in calcium homeostasis, damage of myo-
cardial mitochondrion and alteration of molecular signalling
[2,3]. Free-radical-mediated damage is thought to be the most
severe adverse effect [1,3]. Doxorubicin generates oxygen radicals
either by itself or by forming a complex with ions, and the cardiac
tissues are highly susceptible to such oxidative damage due
to the insufficient capability of eliminating these radicals .
Screening antioxidants for protective effects against the
doxorubicin-induced cardiotoxicity has become a trend
recently . Although some antioxidants, such as vitamin E
and N-acetylcysteine, work well both
models, they fail to eliminate oxygen radicals in clinical
patients [4–6]. Recently, some researchers have focused on
natural antioxidants to find anticipants that can alleviate the
doxorubicin-induced cardiotoxicity without compromising
the antitumour activity of doxorubicin.
and in animal
The radix of
medicine, inhibits platelet conglomeration, promotes genera-
tion of red cells, scavenges oxygen radical and influences
cell proliferation . Water extract of
been reported to inhibit FeCl
(MDA, a marker of lipid peroxidation) formation in rat
observed to be able to scavenge oxygen radical and inhibit
reactive oxygen species-induced lipid peroxidation in mice
liver homogenate .
The effect of
on doxorubicin-induced oxida-
tive stress was evaluated by the levels of MDA and super-
oxide dismutase (SOD) in cardiac tissues. Our objective is
to find whether there is reduction of lipid peroxidation
and increase of antioxidant enzymes, which supports the
antioxidant effect of
induced oxidative stress. Because electrocardiograph
(ECG) has been applied to detect cardiotoxicity of doxoru-
bicin [10,11], we also performed echocardiogram to detect
whether pre-treatment with
doxorubicin-induced conduction abnormalities. Because
doxorubicin triggers the disruption of cardiac myocytes
and the release of intracellular creatine kinase (CK) and
aspartate aminotransferase (AST) into serum , the
on the change of serum CK and AST
caused by doxorubicin were also examined. Finally, the
protective effect of
myocardial injury was investigated by histopathological
, a Chinese traditional
responding to doxorubicin-
would improve the
Author for correspondence: Yao-Xian Xuan, State Key Laboratory
of Safety Evaluation for New Drugs, Zhejiang Academy of Medical
Sciences, 182 Tianmushan Road, Hangzhou 310013, Zhejiang,
China (fax +86 571 8886 0055, e-mail email@example.com).
*These authors contributed equally to this work.
YAN-FEI XIN ET AL.
© 2007 The Authors
Journal compilation © 2007 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 101, 421–426
in H9c2 cells: role of glutathione synthesis and regeneration.
Planta Med 2007;73:134–41
24 Green PS, Leeuwenburgh C. Mitochondrial dysfunction is an
early indicator of doxorubicin-induced apoptosis. Biochim Biophys
25 Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C.
Doxorubicin treatment in vivo causes cytochrome C release and
cardiomyocyte apoptosis, as well as increased mitochondrial
efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio.
Cancer Res 2002;62:4592–8.
26 Sun LQ. Modern research on chemistry, pharmacology,
pharmacokinetics, toxicity, and clinical application of Radix
Angelica sinensis. Asian J Drug Metab Pharm 2005;5:265–81.
27 Kuang X, Yao Y, Du JR, Liu YX, Wang CY, Qian ZM. Neuro-
protective role of Z-ligustilide against forebrain ischemic injury
in ICR mice. Brain Res 2006;1102:145–53.