The ferroptosis inducer erastin irreversibly inhibits system x(c)- and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells.
The ferroptosis inducer erastin irreversibly inhibits system x(c)- and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells.
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非可逆性诱导剂Erastin不可逆地抑制了系统X（C），并与顺铂协同以增加顺铂在癌细胞中的细胞毒性。
DOI：
10.1038/s41598-018-19213-4
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发表时间：
2018-01-17
影响因子：
4.6
通讯作者：
Sato H
中科院分区：
文献类型：
--
作者：
Sato M;Kusumi R;Hamashima S;Kobayashi S;Sasaki S;Komiyama Y;Izumikawa T;Conrad M;Bannai S;Sato H
系统xc-最近被描述为一种新形式的调节性坏死细胞死亡（称为铁凋亡）的最上游节点。在这种情况下，据报道小分子erastin靶向和抑制系统xc−，导致半胱氨酸饥饿，谷胱甘肽耗尽，从而导致铁凋亡细胞死亡。虽然erastin对xc−系统的抑制作用已被充分证明，但其作用机制尚不清楚。因此，我们试图更详细地询问erastin的促铁作用的潜在机制。当与一些众所周知的系统xc−的抑制剂相比，erastin是最有效的抑制剂在低微摩尔浓度下发挥作用。值得注意的是，只有很短的暴露于低erastin浓度的细胞足以引起系统xc−的强烈和持久的抑制，导致谷胱甘肽耗尽。这些对系统xc−的抑制作用不涉及转运蛋白的半胱氨酸修饰。更重要的是，肿瘤细胞与erastin的短时间暴露强烈增强了顺铂的细胞毒性作用，从而有效地根除肿瘤细胞。因此，我们的数据表明，只有很短的erastin预处理足以与顺铂协同有效地诱导癌细胞死亡，这一发现可能指导我们设计新的癌症治疗模式。
System xc− was recently described as the most upstream node in a novel form of regulated necrotic cell death, called ferroptosis. In this context, the small molecule erastin was reported to target and inhibit system xc−, leading to cysteine starvation, glutathione depletion and consequently ferroptotic cell death. Although the inhibitory effect of erastin towards system xc− is well-documented, nothing is known about its mechanism of action. Therefore, we sought to interrogate in more detail the underlying mechanism of erastin’s pro-ferroptotic effects. When comparing with some well-known inhibitors of system xc−, erastin was the most efficient inhibitor acting at low micromolar concentrations. Notably, only a very short exposure of cells with low erastin concentrations was sufficient to cause a strong and persistent inhibition of system xc−, causing glutathione depletion. These inhibitory effects towards system xc− did not involve cysteine modifications of the transporter. More importantly, short exposure of tumor cells with erastin strongly potentiated the cytotoxic effects of cisplatin to efficiently eradicate tumor cells. Hence, our data suggests that only a very short pre-treatment of erastin suffices to synergize with cisplatin to efficiently induce cancer cell death, findings that might guide us in the design of novel cancer treatment paradigms.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.8
作者：
Mastroberardino, L;Spindler, B;Verrey, F
通讯作者：
Verrey, F
影响因子：
11.4
作者：
Gout, PW;Kang, YJ;Buckley, AR
通讯作者：
Buckley, AR
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
6.6
作者：
Lewerenz, Jan;Baxter, Paul;Maher, Pamela
通讯作者：
Maher, Pamela