Emanuelov Avishag K, Shainberg Asher, Chepurko Yelena, Kaplan Doron, Sagie Alex, Porat Eyal, Arad Michael, Hochhauser Edith
Gonda (Goldschmied) Medical Diagnostic Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Biochem Pharmacol. 2010 Jan 15;79(2):180-7. doi: 10.1016/j.bcp.2009.08.010. Epub 2009 Aug 15.
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 A(3) adenosine receptor (A(3)R), 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 Ca(2+) accumulation induced by DOX. Rats were injected every alternate day (6 times) with (1) saline, (2) 2.5mg/kg i.p. DOX, (3) 33 microg/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 Ca(2+) 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 Ca(2+) levels in the cytosol and in mitochondria by diminishing the SR Ca(2+) uptake. Pretreatment with Cl-IB-MECA attenuated left ventricular dysfunction, improved SR calcium storage capacity and prevented mitochondrial Ca(2+) overload. We conclude that the adenosine A(3) receptor agonist is effective in vivo against DOX cardiotoxicity via the restoration of Ca(2+) homeostasis and prevention of mitochondrial damage that occurs as a result of Ca(2+) overload.
与阿霉素（DOX）治疗相关的心脏毒性限制了这种药物对癌症的治疗效果。2-氯-N(6)-(3-碘苄基)腺苷-5'-N-甲基脲酰胺（Cl-IB-MECA），一种A(3)腺苷受体（A(3)R）的选择性激动剂，可降低新生大鼠培养心肌细胞中的DOX毒性。该研究的目的是确定Cl-IB-MECA所显示的保护作用是否能减轻体内的心脏抑制。此外，我们希望研究这种保护途径是否会影响肌浆网（SR）的钙摄取和释放，以及DOX诱导的线粒体内Ca(2+)积累。大鼠每隔一天注射（共6次）：（1）生理盐水，（2）2.5mg/kg腹腔注射DOX，（3）33μg/kg静脉注射Cl-IB-MECA，（4）DOX+Cl-IB-MECA。在注射期结束时和4周后，通过侵入性（压力）和非侵入性（超声心动图）技术评估左心室功能。用indo-1和rhod-2探针测量细胞质和线粒体内的钙水平。通过将培养的大鼠心肌细胞暴露于咖啡因来测定SR Ca(2+)含量。超声心动图数据显示，与对照组相比，DOX治疗的动物左心室壁变薄（23%），收缩末期内径增加（170%），缩短分数降低（35±5%对54±5%，p<0.01）。DOX通过减少SR Ca(2+)摄取增加了细胞质和线粒体中的Ca(2+)水平。用Cl-IB-MECA预处理可减轻左心室功能障碍，改善SR钙储存能力，并防止线粒体Ca(2+)过载。我们得出结论，腺苷A(3)受体激动剂通过恢复Ca(2+)稳态和预防因Ca(2+)过载而发生的线粒体损伤，在体内对DOX心脏毒性有效。
