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Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity.

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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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

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

    ,

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

    ,

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

    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbasia, Cairo, Egypt. ebtehal_dm@yahoo.com.

    Source

    Cancer chemotherapy and pharmacology 77:2 2016 Feb pg 309-22

    MeSH

    Adenosine
    Animals
    Antibiotics, Antineoplastic
    Cardiotonic Agents
    Cardiotoxicity
    Doxorubicin
    Hemodynamics
    Immunohistochemistry
    Male
    Myocardium
    Oxidative Stress
    Rats
    Rats, Wistar
    Receptor, Adenosine A3

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    26676227

    Citation

    Galal, Aya, et al. "Selective A3 Adenosine Receptor Agonist Protects Against Doxorubicin-induced Cardiotoxicity." Cancer Chemotherapy and Pharmacology, vol. 77, no. 2, 2016, pp. 309-22.
    Galal A, El-Bakly WM, Al Haleem EN, et al. Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol. 2016;77(2):309-22.
    Galal, A., El-Bakly, W. M., Al Haleem, E. N., & El-Demerdash, E. (2016). Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemotherapy and Pharmacology, 77(2), pp. 309-22. doi:10.1007/s00280-015-2937-y.
    Galal A, et al. Selective A3 Adenosine Receptor Agonist Protects Against Doxorubicin-induced Cardiotoxicity. Cancer Chemother Pharmacol. 2016;77(2):309-22. PubMed PMID: 26676227.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. AU - Galal,Aya, AU - El-Bakly,Wesam M, AU - Al Haleem,Ekram Nemr Abd, AU - El-Demerdash,Ebtehal, Y1 - 2015/12/16/ PY - 2015/09/22/received PY - 2015/11/30/accepted PY - 2015/12/18/entrez PY - 2015/12/18/pubmed PY - 2016/6/28/medline KW - Adenosine A3 receptor agonist KW - Cardiotoxicity KW - Doxorubicin KW - Oxidative stress SP - 309 EP - 22 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 77 IS - 2 N2 - 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. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/26676227/Selective_A3_adenosine_receptor_agonist_protects_against_doxorubicin_induced_cardiotoxicity_ L2 - https://dx.doi.org/10.1007/s00280-015-2937-y DB - PRIME DP - Unbound Medicine ER -