Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway
Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway
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硒代胱氨酸通过触发活性氧介导的 DNA 损伤和 ERK 通路失活，增强 5-氟尿嘧啶诱导的癌细胞凋亡
DOI：
10.1016/j.freeradbiomed.2013.07.002
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发表时间：
2013-12-01
影响因子：
7.4
通讯作者：
Chen, Tianfeng
中科院分区：
文献类型：
--
作者：
Fan, Cundong;Chen, Jingjing;Chen, Tianfeng
基于 5-氟尿嘧啶 (5-FU) 的化疗作为一线治疗方法相当有限，因为其效率低下且临床耐药。寻找可以提高其效率并克服对 5-FU 耐药性的化学增敏剂引起了科学家的极大兴趣。硒代胱氨酸（SeC）是一种天然存在的硒氨基酸，在我们之前的研究中表现出广谱抗癌活性。这项研究表明，SeC 通过诱导线粒体介导的细胞凋亡，并参与 DNA 损伤介导的 p53 磷酸化和 ERK 失活，作为 5-FU 诱导的 A375 人黑色素瘤细胞细胞凋亡的有效增强剂。用 SeC 预处理细胞，通过调节 Bcl-2 家族蛋白的表达水平，显着增强 5-FU 诱导的线粒体膜电位损失 (Delta psi(m))。 SeC 和 5-FU 组合还通过调节细胞内氧化还原系统引发细胞氧化应激，导致 DNA 损伤和 ERK 和 AKT 失活。此外，ERK和AKT抑制剂有效增强联合治疗诱导的细胞凋亡。然而，用谷胱甘肽预处理细胞可逆转SeC和5-FU诱导的细胞凋亡，并恢复ERK和AKT失活的表达，这揭示了活性氧在细胞凋亡和ERK和AKT通路调节中的重要作用。综上所述，我们的结果表明，联合使用 SeC 和 5-FU 的策略可能是实现抗癌协同作用的高效方法。 (C) 2013 Elsevier Inc. 保留所有权利。
5-Fluorouracil (5-FU)-based chemotherapy as a first-line treatment is quite limited, because of its inefficiency and clinical resistance to it. The search for chemosensitizers that could augment its efficiency and overcome the drug resistance to 5-FU has kindled great interest among scientists. Selenocystine (SeC), a naturally occurring selenoamino acid, displayed broad-spectrum anticancer activity in our previous studies. This study demonstrates that SeC acts as an effective enhancer of 5-FU-induced apoptosis in A375 human melanoma cells through induction of mitochondria-mediated apoptosis with the involvement of DNA damage-mediated p53 phosphorylation and ERK inactivation. Pretreatment of the cells with SeC significantly enhanced 5-FU-induced loss of mitochondrial membrane potential (Delta psi(m)) by regulating the expression levels of Bcl-2 family proteins. SeC and 5-FU in combination also triggered cell oxidative stress through regulation of the intracellular redox system and led to DNA damage and inactivation of ERK and AKT. Moreover, inhibitors of ERK and AKT effectively enhanced the apoptotic cell death induced by the combined treatment. However, pretreatment of the cells with glutathione reversed the apoptosis induced by SeC and 5-FU and recovered the expression of ERK and AKT inactivation, which revealed the important role of reactive oxygen species in cell apoptosis and regulation of ERK and AKT pathways. Taken together, our results suggest that a strategy of using SeC and 5-FU in combination could be a highly efficient way to achieve anticancer synergism. (C) 2013 Elsevier Inc. All rights reserved.