ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.
ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.
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DOI：
10.1007/s10549-011-1568-1
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发表时间：
2012-02
影响因子：
3.8
通讯作者：
Devi, Gayathri R.
中科院分区：
文献类型：
--
作者：
Aird, Katherine M.;Allensworth, Jennifer L.;Batinic-Haberle, Ines;Lyerly, H. Kim;Dewhirst, Mark W.;Devi, Gayathri R.
关键词：
表皮生长因子受体（ErbB）的过度表达常见于炎性乳腺癌（IBC）。ErbB 1/2靶向药物（拉帕替尼）治疗通过下调ErbB 1/2磷酸化和下游生存信号介导肿瘤凋亡。在这项研究中，使用羧基-H2 DCFDA，DHE和MitoSOX Red分别检查过氧化氢自由基，细胞质和线粒体超氧化物的变化，我们观察到GW 583340（拉帕替尼类似物）在两种对ErbB 1/2阻断敏感的IBC模型（SUM 149，SUM 190）中增加活性氧（ROS）。ROS水平的这种显著增加与经典氧化剂H2 O2和百草枯产生的ROS水平相似。相反，在GW 583340抗性IBC细胞（rSUM 149和rSUM 190）的克隆群体中测量到最小至基础水平的ROS。GW 583340耐药的IBC细胞表现出增加的SOD 1，SOD 2和谷胱甘肽的表达，这与GW 583340，H2 O2和百草枯的抗肿瘤诱导作用的敏感性降低。ROS的增加和细胞死亡的GW 583340敏感的细胞被逆转，同时处理与超氧化物歧化酶（SOD）模拟。此外，使用氧化还原调节剂克服高水平的抗氧化剂诱导了GW 583340抗性细胞的凋亡。总之，这些数据证明了拉帕替尼类似物诱导细胞凋亡的新机制，并表明耐药细胞具有增加的抗氧化潜力，这可以通过用SOD调节剂治疗来克服。
Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H2DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H2O2 and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H2O2, and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.
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影响因子：
5.7
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
通讯作者：
Devi, Gayathri R.
影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
6.1
作者：
Khan, Gazala;Merajver, Sofia
通讯作者：
Merajver, Sofia
影响因子：
11.2
作者：
Contreras, Cristina M.;Gurumurthy, Sushma;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.
DOI：
10.1006/bbrc.2001.5544
发表时间：
2001-09-14
影响因子：
3.1
作者：
Choi, SL;Kim, SJ;Ha, J
通讯作者：
Ha, J