Excessive Oxidative Stress in the Synergistic Effects of Shikonin on the Hyperthermia-Induced Apoptosis
Excessive Oxidative Stress in the Synergistic Effects of Shikonin on the Hyperthermia-Induced Apoptosis
复制标题
DOI：
10.2174/1566524018666181024161704
复制
发表时间：
2018-01-01
影响因子：
2.5
通讯作者：
Inadera, H.
中科院分区：
文献类型：
--
作者：
Piao, J-L;Jin, Y-J;Inadera, H.
背景：热疗（HT）已被广泛用于癌症治疗，现代设备的发展使其更加有效。紫草素（Shikonin，SHK）是一种天然的萘醌类化合物，其抗肿瘤作用已被证实，但其分子机制尚未完全阐明。目的：研究低剂量SHK与温和的HT联合应用对U937细胞的作用。在有或没有SHK预处理的情况下，使细胞在44 ° C下经受HT 10分钟，并且通过使用DNA片段化、流式细胞术、流式细胞术、细胞计数和细胞内钙升高来评估反映细胞凋亡、ROS产生和细胞内钙升高的参数。结果：SHK 0.5 μ M可显著增强HT诱导的细胞凋亡，表现为DNA断裂和caspase-3激活，同时增加ROS的产生和细胞内钙离子浓度。联合治疗还协同激活促凋亡蛋白和灭活抗凋亡蛋白。此外，JNK和PKC-δ的磷酸化以及ERK和AKT的去磷酸化是可能复合了凋亡诱导的上游效应。HT和SHK的调节作用被NAC和JNK-IN-8通过失活MAPK通路和切割caspase-3而废除。细胞内钙离子也升高，并被认为是负责诱导细胞死亡的DNA片段与或没有就业的BAPTA-AM。结论：总之，这项研究提供了有说服力的证据表明，SHK与HT相结合是一个有利的治疗方式，增加细胞凋亡，因此提出了一种新的治疗癌症的策略。
Background: Hyperthermia (HT) has been used widely for cancer therapy, and the development of modern devices has made it more efficient. Shikonin (SHK) is a natural naphthoquinone derivative from a Chinese herb. Although the anticancer properties of SHK are evident, the underlying molecular mechanisms are not fully understood.Objective: In this study, the effects of combining low doses of SHK with mild HT were investigated in the U937 cell line.Methods: The cells were subjected to HT at 44 degrees C for 10 min with or without SHK pretreatment, and parameters reflecting apoptosis, ROS generation and intracellular calcium elevation were evaluated by using DNA fragmentation, flow cytometry, and western blot analyses.Results: SHK 0.5 mu M significantly enhanced HT-induced apoptosis as indicated by DNA fragmentation and caspase-3 activation with increased generation of ROS and elevation of intracellular calcium. The combined treatment also synergistically activated proapoptotic proteins and inactivated anti-apoptotic proteins. Furthermore, the phosphorylation of JNK and PKC-delta and the dephosphorylation of ERK and AKT were the upstream effects that may have compounded the induction of apoptosis. The modulatory effects of HT and SHK were abrogated with the employment of NAC and JNK-IN-8 by inactivating the MAPK pathway and cleavage of caspase-3. Intracellular calcium was also elevated and was found to be responsible for the induction of cell death evident by the DNA fragmentation with or without the employment of BAPTA-AM.Conclusion: Conclusively, this study provides persuasive evidence that SHK in combination with HT is a propitious therapeutic way for augmentation of apoptosis and hence suggest a novel strategy for treating cancers.