Concomitant low-dose doxorubicin treatment and exercise
Concomitant low-dose doxorubicin treatment and exercise
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DOI：
10.1152/ajpregu.00082.2014
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发表时间：
2014-09-15
影响因子：
2.8
通讯作者：
Libonati, Joseph R.
中科院分区：
文献类型：
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作者：
Sturgeon, Kathleen;Schadler, Keri;Libonati, Joseph R.
心脏毒性是多柔比星（DOX）治疗癌症患者的副作用。我们验证了低强度有氧运动联合DOX治疗可以抵消DOX诱导的心脏毒性，同时提高DOX对肿瘤进展的治疗效果的假设。将B16F10黑色素瘤细胞（3 × 10(5)）皮下注射到6 ~ 8周龄雄性C57BL/6小鼠（n = 48）的颈部。DOX的累积剂量为4mg /kg，持续2周，运动（EX）包括跑步机步行（10米/分钟，45分钟/天，5天/周，2周）。实验分为四个实验组：1)久坐(SED) +载具，2)SED + DOX, 3) EX +载具，4)EX + DOX。DOX组肿瘤体积减小，EX + DOX组肿瘤体积最小。dox处理动物的体重增加较少，心脏重量（HW）减少，心脏重量与体重的比率较小，胫骨长度较短；和运动并不能逆转DOX的心脏毒性作用。尽管DOX降低了左心室（LV）质量，但心肌细胞横截面积、β -肌球蛋白重链基因表达、全心收缩（分数缩短）和舒张（E/A比）功能在各组之间相似。DOX也导致左室纤维化增加，左室舒张末期容积和卒中容积降低。心肌蛋白激酶B活性在DOX和EX处理下均升高，结节性硬化症2 （TSC2）丰度在EX处理下降低。TSC2的下游磷酸化和哺乳动物雷帕霉素靶蛋白在各组之间相似。我们得出结论，在小鼠黑色素瘤模型中，运动增加了DOX抑制肿瘤生长的功效，但没有减轻DOX诱导的亚临床心脏毒性。
Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 x 10(5)) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, beta-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.