Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related
Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related
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DOI：
10.1016/j.tox.2015.03.002
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发表时间：
2015-05-04
期刊：
影响因子：
4.5
通讯作者：
Roth, Robert A.
中科院分区：
文献类型：
--
作者：
Beggs, Kevin M.;Maiuri, Ashley R.;Roth, Robert A.
氟喹诺酮类抗生素曲伐沙星(TVX)由于特殊的药物性肝损伤(IDILI)而受到限制。以往的研究表明，肿瘤坏死因子-α和TVX在体外相互作用导致肝细胞死亡，这与c-jun氨基末端激酶(JNK)的激活延长、caspase9和caspase3的激活以及DNA损伤有关。本研究的目的是进一步探讨TVX与肿瘤坏死因子相互作用产生细胞毒作用的机制。经TVX处理后，细胞周期停滞，p21表达增强，细胞增殖受阻，但细胞死亡仅发生在TVX和肿瘤坏死因子联合作用后。细胞死亡涉及细胞外信号相关激酶(ERK)的激活，进而激活caspase3和共济失调毛细血管扩张和Rad3相关(ATR)，两者都参与了细胞毒作用。用TVX和肿瘤坏死因子共同处理HepG2细胞可引起DNA双链断裂，ERK参与了这一效应。抑制半胱氨酸氨基转移酶活性可使DNA链断裂消失。这些数据表明TVX和肿瘤坏死因子之间存在复杂的相互作用，其中TVX引起复制应激，其下游效应被肿瘤坏死因子加剧，导致肝细胞死亡。这些结果提出了TVX的IDILI可能是由细胞因子信号与药物诱导的复制应激相互作用所启动的肝细胞MAPK和ATR激活所致。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise the possibility that IDILI from TVX results from MAPK and ATR activation in hepatocytes initiated by interaction of cytokine signaling with drug-induced replication stress. (C) 2015 Elsevier Ireland Ltd. All rights reserved.