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Journal of Pharmacology and Therapeutic Research
Volume 1 Issue 1
Clinical Pharmacy 2017
Page 49
December 07-09, 2017 | Rome, Italy
7
th
World Congress on
Clinical Pharmacy and Pharmacy Practice
5-Fluorouracil cardiotoxicity: Molecular
mechanisms and protective effects of
simvastatin
Mohammed R, Sallam N
and
El-Abhar H
Cairo University, Egypt
Background:
5-fluorouracil (5-FU) is a chemotherapeutic
agent widely used in the treatment of different solid
tumours, especially colorectal cancer. Its use is associated
with rare but potentially serious cardiovascular toxicity.
This study aims to investigate molecular mechanisms
underlying the cardiovascular toxicity of 5-FU and the
potential protective effects of simvastatin.
Methods:
Adult male albino Wistar rats were randomly
divided into four groups (15-20/group). The first group
received normal saline (i.p) once weekly for six successive
weeks. In the second group rats received 5-FU (50 mg/
kg; i.p) once weekly for six successive weeks (cardiotoxic
group). Rats of the third group received simvastatin (15
mg/kg/day, p.o.) daily for eight successive weeks. Finally,
rats of the forth group received simvastatin daily a week
before the first 5-FU injection, then concomitantly for six
weeks, and continued alone for another week after the
last dose of 5-FU. ECG recording was weekly carried
out. Cardiac content of NADPH-oxidase, COX-2, NF-
kB, p-eNOS and p-AKT in addition to aortic content of
endothelin-1 and thromboxane-A2 were assessed by
enzyme-linked immunosorbent assay. Protein expression
of cardiac caspase-3 and Rho-kinase was evaluated by
western blotting. Serum level of NT-proBNP and cardiac
TBARS (thiobarbituric acid reactive substances) were
also evaluated. Finally, histopathological evaluation of
both cardiac and aortic tissues was carried out.
Results:
5-FU caused histopathological changes in both
myocardial and aortic tissues. Myocardial ischemia and
QTc prolongation were confirmed by ECG recording.
5-FU increased myocardial NADPH-oxidase and
COX-2 content, leading to increased ROS production.
Oxidative stress, inflammation and associated apoptosis
in the heart were indicated by elevated TBARS, NF-kB
content and caspase-3 protein expression, respectively.
Elevated aortic tissue content of endothelin-1 and
thromboxane-A2, the two potent vasoconstrictors was
observed. 5-FU significantly increased ROCK protein
expression and p-AKT content, and suppressed p-eNOS
level. Finally, elevated serum level of NT-proBNP was
observed. Simvastatin was able to prevent most of these
abnormalities.
Conclusion:
Direct myocardial injury and ischemia
caused by endothelial dysfunction and activation of
Rho/ROCK pathway are potential mechanisms of 5-FU
cardiovascular toxicity. Inhibition of ROCK activity by
simvastatin, a drug with potent antioxidant and pleiotropic
properties, mitigates the cardiovascular toxicity of 5-FU.
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Mohammed R et al., J Pharmacol Ther Res 2017