Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Free Radic Biol Med. 2012 Apr 15;52(8):1285-93. doi: 10.1016/j.freeradbiomed.2012.02.003. Epub 2012 Feb 11.
Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and L-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.
表阿霉素是一种蒽环类抗肿瘤药物，常引起血管损伤，如血管痛、静脉炎和坏死性血管炎。然而，尚未建立有效的表阿霉素引起的血管损伤预防措施。本研究的目的是确定表阿霉素在猪主动脉内皮细胞（PAECs）中诱导细胞损伤的机制。PAECs 暴露于表阿霉素 10 分钟，然后在无表阿霉素的情况下进一步孵育。表阿霉素（3-30 μM）浓度和时间依赖性地降低细胞活力。表阿霉素增加了 caspase-3/7 的活性、凋亡细胞和细胞内脂质过氧化物水平，并导致线粒体膜去极化。这些细胞内事件被谷胱甘肽（GSH）和 N-乙酰半胱氨酸（NAC）逆转，而表阿霉素轻微增加细胞内 GSH，而 L-丁硫氨酸-（S，R）-亚砜，一种 GSH 合成的特异性抑制剂，对表阿霉素诱导的细胞损伤没有影响。p38 丝裂原活化蛋白激酶（MAPK）抑制剂 SB203580 和 PD169316 也减弱了表阿霉素诱导的细胞损伤和 caspase-3/7 活性的增加。此外，表阿霉素显著增强了 p38 MAPK 的磷酸化，这些作用被 GSH 和 NAC 减弱。相比之下，c-Jun N 末端激酶抑制剂 SP600125、细胞外信号调节激酶抑制剂 PD98059 和 p53 抑制剂 pifithrin α 不影响表阿霉素诱导的细胞损伤和 caspase-3/7 活性的增加。这些结果表明，氧化应激引起的 p38 MAPK 激活参与了表阿霉素诱导的内皮细胞损伤。
