NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway.
NV-128, a novel isoflavone derivative, induces caspase-independent cell death through the Akt/mammalian target of rapamycin pathway.
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DOI：
10.1002/cncr.24397
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发表时间：
2009-07-15
期刊：
影响因子：
6.2
通讯作者：
Mor, Gil
中科院分区：
文献类型：
--
作者：
Alvero, Ayesha B.;Montagna, Michele K.;Chen, Rui;Kim, Ki Hyung;Kyungjin, Kim;Visintin, Irene;Fu, Han-Hsuan;Brown, David;Mor, Gil
对凋亡的抵抗是赋予化学抵抗的关键事件之一，并且通过抑制半胱天冬酶激活的抗凋亡蛋白的过表达来介导。本研究的目的是评估是否激活替代细胞死亡途径（半胱天冬酶非依赖性）可以促进化疗耐药卵巢癌细胞的死亡。我们报告了NV-128通过半胱天冬酶非依赖性途径诱导细胞死亡的特征。用递增浓度的NV-128处理上皮性卵巢癌细胞（EOC）的原代培养物，并使用细胞滴度96测定法测定GI 50。通过蛋白质印迹分析、半胱天冬酶Glo测定、免疫组织化学和流式细胞术表征凋亡蛋白。使用免疫沉淀法测定蛋白质-蛋白质相互作用。在异种移植小鼠模型中测量体内活性。NV-128能够在GI 50为1至5 μ g/ml的紫杉醇和卡铂抗性EOC细胞中诱导显著的细胞死亡。细胞死亡的特点是染色质凝聚，但半胱天冬酶的独立性。激活的途径涉及磷酸化AKT、磷酸化mTOR和磷酸化S6激酶的下调，以及Beclin-1的线粒体易位，随后是EndoG的核易位。我们已经表征了一种新型化合物，其抑制mTOR并促进非半胱天冬酶依赖性细胞死亡。我们的研究结果表明，抑制mTOR可能代表了一个相关的途径诱导细胞死亡的细胞抵抗经典的半胱天冬酶依赖性凋亡。这些发现证明了使用治疗药物的可能性，如NV-128，这可能对化疗耐药的卵巢癌患者产生有益的影响。
Resistance to apoptosis is one of the key events that confer chemo-resistance and is mediated by over-expression of anti-apoptotic proteins, which inhibit caspase activation. The objective of this study was to evaluate whether the activation of an alternative cell death pathway (caspase-independent) could promote death in chemo-resistant ovarian cancer cells. We report the characterization of NV-128 as an inducer of cell death through a caspase-independent pathway. Primary cultures of epithelial ovarian cancer cells (EOC) were treated with increasing concentration of NV-128 and GI50 was determined using Cell titer 96 assay. Apoptotic proteins were characterized by western blot analyses, Caspase Glo assays, immunohistochemistry, and flow cytometry. Protein-protein interactions were determined using immunoprecipitation. In vivo activity was measured in a xenograft mice model. NV-128 is able to induce significant cell death in both Paclitaxel- and Carboplatin- resistant EOC cells with GI50 between 1 and 5 ug/ml. Cell death was characterized by chromatin condensation but was caspase-independent. The activated pathway involved the down-regulation of phospho-AKT, phospho- mTOR, and phospho-S6 kinase, and the mitochondrial translocation of Beclin-1 followed by nuclear translocation of EndoG. We have characterized a novel compound, which inhibits mTOR and promotes caspase-independent cell death. Our results indicate that inhibition of mTOR may represent a relevant pathway for induction of cell death in cells resistant to the classical caspase-dependent apoptosis. These findings demonstrate the possibility of using therapeutic drugs, such as NV-128, which could have beneficial effects in chemo-resistant ovarian cancer patients.
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影响因子：
11.2
作者：
Kelly, MG;Alvero, AB;Mor, G
通讯作者：
Mor, G
影响因子：
5.3
作者：
Fingar, DC;Richardson, CJ;Blenis, J
通讯作者：
Blenis, J
影响因子：
7.4
作者：
Kluger, Harriet M.;McCarthy, Mary M.;Alvero, Ayesha B.;Sznol, Mario;Ariyan, Stephan;Camp, Robert L.;Rimm, David L.;Mor, Gil
通讯作者：
Mor, Gil
影响因子：
3.7
作者：
Furuya, D;Tsuji, N;Watanabe, N
通讯作者：
Watanabe, N
影响因子：
6.2
作者：
Alvero, AB;O'Malley, D;Mor, G
通讯作者：
Mor, G