Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells
Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells
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DOI：
10.1074/jbc.m108084200
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发表时间：
2002-05-24
影响因子：
4.8
通讯作者：
Kasuya, M
中科院分区：
文献类型：
--
作者：
Arai, Y;Kondo, T;Kasuya, M
体温过高的综合影响。研究了44 ℃和局麻药对人组织细胞性淋巴瘤U937细胞凋亡的影响。当细胞暴露于高温10分钟时，观察到边缘DNA断裂和核断裂。在酰胺型局部麻醉剂的存在下，发现依赖于浓度的进一步增强。最大诱导所需的浓度顺序是亲脂性的相反顺序（丙胺卡因>利多卡因>布比卡因）。蛋白质印迹法显示，在高温有初始释放的Ca 2+从细胞内存储网站所示的1型肌醇-1，4，5-三磷酸受体的表达增加。然而，与利多卡因的组合没有引起任何进一步的增强。利多卡因可增强高温引起的细胞内ATP含量的降低和细胞内Ca ~（2+）浓度的升高。此外，超氧化物的形成，线粒体膜电位的下降，和细胞内的caspase-3的激活被发现在高温和利多卡因处理的细胞。所有这些都在细胞内Ca 2+离子螯合剂BAPTA-AM（双-（O-氨基苯氧基）-乙烷-N，N，N '，N'-四乙酸-乙酰氧基甲基）存在下部分抑制。本研究结果表明，局部麻醉药在最佳浓度下通过Ca 2+和Ca 2+依赖性途径增强高血压诱导的细胞凋亡。由高温引起的细胞内储存位点的Ca 2+的初始释放以及随后的细胞内Ca 2+浓度的增加和线粒体半胱天冬酶依赖性途径（部分受细胞内Ca 2+浓度调节）的额外激活在高温和利多卡因组合诱导的细胞凋亡的增强中起着至关重要的作用。
The combined effects of hyperthermia. at 44 degreesC and local anesthetics on apoptosis in human histiocytic lymphoma U937 cells were investigated. When the cells were exposed to hyperthermia for 10 min marginal DNA fragmentation and nuclear fragmentation were observed. In the presence of amide-type local anesthetics further enhancement was found depending on concentration. The order of the concentration required for maximum induction was the reverse order of the lipophilicity (prilocaine > lidocaine > bupivacaine). Western blotting revealed that in hyperthermia there was initial release of Ca2+ from the intracellular store site as indicated by increased expression of the type 1 inositol-1,4,5-trisphosphate receptor. However, the combination with lidocaine did not induce any further enhancement. Lidocaine enhanced the decrease in ATP content and the increase in intracellular Ca2+ concentration in individual cells induced by hyperthermia. In addition, superoxide formation, decrease in the mitochondrial membrane potential, and activation of intracellular caspase-3 were found in the cells treated with hyperthermia and lidocaine. All of these were suppressed in part in the presence of the intracellular Ca2+ ion chelator BAPTA-AM (bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl). The present results indicate that local anesthetics at optimal concentrations enhance hyperthermia-induced apoptosis via Ca2+- and mitochondria-dependent pathways. Initial release of Ca2+ from intracellular store sites caused by hyperthermia and followed by the subsequent increase in the intracellular Ca2+ concentration and the additional activation of the mitochondrial caspase-dependent pathway (partly regulated by intracellular Ca2+ concentration) plays a crucial role in the enhancement of apoptosis induced by the combination of hyperthermia and lidocaine.