当前位置: X-MOL 学术Cancer Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting antioxidant enzymes enhances the therapeutic efficacy of the BCL-XL inhibitor ABT-263 in KRAS-mutant colorectal cancers
Cancer Letters ( IF 9.7 ) Pub Date : 2020-10-15 , DOI: 10.1016/j.canlet.2020.10.018
Yumi Oh , Hae Rim Jung , Seoyeon Min , Jinjoo Kang , Dongjun Jang , Seungjae Shin , Jiwon Kim , Sang Eun Lee , Chang Ohk Sung , Won-Suk Lee , Charles Lee , Eui Man Jeong , Sung-Yup Cho

Cancer chemotherapeutic drugs exert cytotoxic effects by modulating intracellular reactive oxygen species (ROS) levels. However, whether ROS modulates the efficacy of targeted therapeutics remains poorly understood. Previously, we reported that upregulation of the anti-apoptotic protein, BCL-XL, by KRAS activating mutations was a potential target for KRAS-mutant colorectal cancer (CRC) treatment. Here, we demonstrated that the BCL-XL targeting agent, ABT-263, increased intracellular ROS levels and targeting antioxidant pathways augmented the therapeutic efficacy of this BH3 mimetic. ABT-263 induced expression of genes associated with ROS response and increased intracellular ROS levels by enhancing mitochondrial superoxide generation. The superoxide dismutase inhibitor, 2-methoxyestradiol (2-ME), exhibited synergism with ABT-263 in KRAS-mutant CRC cell lines. This synergistic effect was attributed to the inhibition of mTOR-dependent translation of the anti-apoptotic MCL-1 protein via caspase 3-mediated cleavage of AKT and S6K. In addition, combination treatment of ABT-263 and 2-ME demonstrated a synergistic effect in in vivo patient-derived xenografts harboring KRAS mutations. Our data suggest a novel role for ROS in BH3 mimetic-based targeted therapy and provide a novel strategy for treatment of CRC patients with KRAS mutations.



中文翻译:

靶向抗氧化酶增强了BCL-X的治疗功效大号在抑制剂ABT-263 KRAS -mutant结肠直肠癌

癌症化疗药物通过调节细胞内活性氧(ROS)的水平发挥细胞毒性作用。但是,ROS是否能调节靶向疗法的疗效仍知之甚少。此前,我们报道了抗凋亡蛋白BCL-X的表达上调大号,通过KRAS的活化突变是一个潜在的目标KRAS -mutant结直肠癌(CRC)的治疗。在这里,我们证明了BCL-X L靶向剂ABT-263,增加了细胞内ROS水平,靶向抗氧化剂途径增强了这种BH3模拟物的治疗效果。ABT-263通过增强线粒体超氧化物生成来诱导与ROS反应相关的基因表达并增加细胞内ROS水平。在KRAS突变的CRC细胞系中,超氧化物歧化酶抑制剂2-甲氧基雌二醇(2-ME)与ABT-263协同作用。这种协同作用归因于通过半胱天冬酶3介导的AKT和S6K的裂解来抑制抗凋亡MCL-1蛋白的mTOR依赖性翻译。此外,ABT-263和2-ME的联合治疗在体内携带KRAS的患者来源异种移植物中显示出协同作用突变。我们的数据表明ROS在基于BH3模拟物的靶向治疗中的新作用,并为治疗具有KRAS突变的CRC患者提供了新的策略。

更新日期:2020-10-30
down
wechat
bug