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Cancer Chemotherapy and Pharmacology

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01.02.2016 | Original Article

Selective A₃ adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity

verfasst von: Aya Galal, Wesam M. El-Bakly, Ekram Nemr Abd Al Haleem, Ebtehal El-Demerdash

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2016

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Abstract

Purpose

Doxorubicin (DOX) is an effective anticancer drug; however, its clinical use is limited by its cardiotoxic effect. Adenosine was proved to mediate anti-inflammatory effects and protected from myocardial ischemia/reperfusion injury. So the present work was designed to examine the effectiveness of a selective A₃ adenosine receptor agonist (Cl-IB-MECA) in DOX-induced cardiotoxicity and to elucidate the underlying mechanisms via studying its effect on different oxidative stress, inflammatory and apoptotic markers.

Methods

Firstly the potential cardioprotective dose of Cl-IB-MECA was screened in male Wistar rats at different doses (20, 40 and 80 µg/kg; i.v) against a single dose of DOX (15 mg/kg; i.p). Secondly, the dose of 40 µg/kg Cl-IB-MECA was selected for further assessment of the cardioprotective mechanisms.

Results

Cl-IB-MECA at a dose 40 µg/kg (i.v) protects against DOX-induced bradycardia, elevated creatine kinase isoenzyme-MB and histopathological changes. Also, it significantly ameliorates oxidative stress injury evoked by DOX as evidenced by inhibition of reduced glutathione depletion and lipid peroxidation as well as elevation of antioxidant enzyme activities. Additionally, DOX provoked inflammatory responses by increasing the expressions of nuclear factor kappa B and the levels of tumor necrosis factor alpha. Cl-IB-MECA pretreatment significantly inhibited these inflammatory responses. Furthermore, DOX induced apoptotic tissue damage by increasing cytochrome c expressions which was suppressed by Cl-IB-MECA pretreatment.

Conclusion

Cl-IB-MECA protects against DOX-induced cardiotoxicity through restoration of the oxidant/antioxidant status and consequential suppression of DOX-induced inflammatory responses and abrogation of the resultant apoptotic signals.

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Titel: Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity
verfasst von: Aya Galal
Wesam M. El-Bakly
Ekram Nemr Abd Al Haleem
Ebtehal El-Demerdash
Publikationsdatum: 01.02.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2016
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2937-y

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Selective A₃ adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity

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