Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage

Avishag K. Emanuelov, Asher Shainberg, Yelena Chepurko, Doron Kaplan, Alex Sagie, Eyal Porat, Michael Arad, Edith Hochhauser

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Cardiotoxicity associated with doxorubicin (DOX) treatment limits the therapeutic efficiency of this drug against cancer. 2-Chloro-N(6)-(3-iodobenzyl)adenosine-5′-N-methyluronamide (Cl-IB-MECA), a selective agonist of A3 adenosine receptor (A3R), reduces DOX toxicity in newborn rat cultured cardiomyocytes. The study's aim was to determine whether the protection demonstrated by Cl-IB-MECA attenuates cardiac depression in vivo. In addition, we wished to examine whether this protective pathway affects the sarcoplasmic reticulum (SR) calcium uptake and release, as well as intramitochondrial Ca2+ accumulation induced by DOX. Rats were injected every alternate day (6 times) with (1) saline, (2) 2.5 mg/kg i.p. DOX, (3) 33 μg/kg i.v. Cl-IB-MECA, (4) DOX + Cl-IB-MECA. Left ventricular functions were assessed by invasive (pressure) and non-invasive (echocardiography) techniques at the end of the injection period and 4 weeks later. Cytosolic and intramitochondrial calcium levels were measured with indo-1 and rhod-2 probes. SR Ca2+ content was determined by exposing cultured rat cardiomyocytes to caffeine. Echocardiography data demonstrate left ventricular wall thinning (23%), an increase in the end systolic dimension (170%) and decreased fractional shortening (35 ± 5% vs. 54 ± 5%, p < 0.01) in DOX-treated animals, compared to the control group. DOX increased Ca2+ levels in the cytosol and in mitochondria by diminishing the SR Ca2+ uptake. Pretreatment with Cl-IB-MECA attenuated left ventricular dysfunction, improved SR calcium storage capacity and prevented mitochondrial Ca2+ overload. We conclude that the adenosine A3 receptor agonist is effective in vivo against DOX cardiotoxicity via the restoration of Ca2+ homeostasis and prevention of mitochondrial damage that occurs as a result of Ca2+ overload.

Original languageEnglish
Pages (from-to)180-187
Number of pages8
JournalBiochemical Pharmacology
Volume79
Issue number2
DOIs
StatePublished - 15 Jan 2010

Bibliographical note

Funding Information:
This research study was conducted through the generous support of The Adar Program for the Advancement of Research in Heart Function and the Horowitz Foundation at Bar-Ilan University.

Keywords

  • A adenosine receptors
  • Ca homeostasis
  • Cl-IB-MECA
  • Doxorubicin

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