Surgery Department, Duke University Medical Center, Durham, North Carolina 27710, USA.
Am J Physiol Heart Circ Physiol. 2012 Sep 1;303(5):H539-48. doi: 10.1152/ajpheart.00108.2012. Epub 2012 Jun 29.
Doxorubicin is commonly used to treat leukemia, lymphomas, and solid tumors, such as soft tissue sarcomas or breast cancer. A major side effect of doxorubicin therapy is dose-dependent cardiotoxicity. Doxorubicin's effects on cardiac energy metabolism are emerging as key elements mediating its toxicity. We evaluated the effect of doxorubicin on [(14)C]creatine uptake in rat neonatal cardiac myocytes and HL-1 murine cardiac cells expressing the human creatine transporter protein. A significant and irreversible decrease in creatine transport was detected after an incubation with 50-100 nmol/l doxorubicin. These concentrations are well below peak plasma levels (5 μmol/l) and within the ranges (25-250 nmol/l) for steady-state plasma concentrations reported after the administration of 15-90 mg/m(2) doxorubicin for chemotherapy. The decrease in creatine transport was not solely because of increased cell death due to doxorubicin's cytotoxic effects. Kinetic analysis showed that doxorubicin decreased V(max), K(m), and creatine transporter protein content. Cell surface biotinylation experiments confirmed that the amount of creatine transporter protein present at the cell surface was reduced. Cardiomyocytes rely on uptake by a dedicated creatine transporter to meet their intracellular creatine needs. Our findings show that the cardiomyocellular transport capacity for creatine is substantially decreased by doxorubicin administration and suggest that this effect may be an important early event in the pathogenesis of doxorubicin-mediated cardiotoxicity.
阿霉素通常用于治疗白血病、淋巴瘤和实体肿瘤，如软组织肉瘤或乳腺癌。阿霉素治疗的一个主要副作用是剂量依赖性的心脏毒性。阿霉素对心脏能量代谢的影响正成为介导其毒性的关键因素。我们评估了阿霉素对[(14)C]肌酸摄取在大鼠新生心肌细胞和表达人类肌酸转运蛋白的 HL-1 鼠心脏细胞中的作用。用 50-100nmol/L 阿霉素孵育后，检测到肌酸转运的显著和不可逆减少。这些浓度远低于峰值血浆水平（5μmol/L），并且在化疗中给予 15-90mg/m(2)阿霉素后报告的稳态血浆浓度范围内（25-250nmol/L）。肌酸转运的减少不仅仅是因为阿霉素的细胞毒性作用导致细胞死亡增加。动力学分析表明，阿霉素降低了 V(max)、K(m)和肌酸转运蛋白含量。细胞表面生物素化实验证实细胞表面的肌酸转运蛋白数量减少。心肌细胞依赖于特定的肌酸转运蛋白摄取来满足其细胞内肌酸需求。我们的发现表明，心肌细胞对肌酸的转运能力因阿霉素的给药而大大降低，这表明这种作用可能是阿霉素介导的心脏毒性发病机制中的一个重要早期事件。
