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Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity

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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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Acknowledgments

We would like to show our gratitude to Mona Hussein Rafeet, Lecturer of Histology, Department of Histology, Faculty of Medicine, Ain Shams University, Egypt, for assistance with Immunohistochemical quantification which was carried out using image analysis software (ImageJ, 1.46a, NIH, USA).

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Authors and Affiliations

  1. Cardiac Surgery Hospital, Ain Shams University, Cairo, Egypt

    Aya Galal

  2. Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Wesam M. El-Bakly

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy for Girls, Al Azhar University, Cairo, Egypt

    Ekram Nemr Abd Al Haleem

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbasia, Cairo, Egypt

    Ebtehal El-Demerdash

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  1. Aya Galal
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  2. Wesam M. El-Bakly
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Correspondence to Ebtehal El-Demerdash.

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Galal, A., El-Bakly, W.M., Al Haleem, E.N.A. et al. Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol 77, 309–322 (2016). https://doi.org/10.1007/s00280-015-2937-y

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  • DOI: https://doi.org/10.1007/s00280-015-2937-y

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