Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells
Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells
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作者：
Alvero, AB;O'Malley, D;Mor, G
背景以前，它被证明，苯氧二醇诱导上皮性卵巢癌（EOC）细胞的凋亡，它是能够敏化这些细胞Fas介导的凋亡。本研究的目的是确定苯恶二醇是否也可以作为化疗药物的化疗增敏剂，并表征其增敏作用背后的分子机制。在本研究中使用了10个EOC细胞系。通过CellTiter 96测定法测定苯氧二醇对卡铂、紫杉醇和吉西他滨的半数抑制浓度（IC 50）的影响。在动物异种移植模型中测定用苯氧二醇和上述药剂的组合治疗的体内效果。使用半胱天冬酶-Glo测定来测量细胞凋亡，并且通过蛋白质印迹分析来表征细胞凋亡级联。结果表明，在体外和体内，苯氧二醇能够使EOC细胞对卡铂、紫杉醇和吉西他滨敏感。此外，酚氧二醇还可通过caspase-2和Bid信号通路激活线粒体途径，以及通过蛋白酶体降解抗凋亡蛋白XIAP来诱导细胞凋亡。了解由苯氧二醇激活的凋亡途径的组分，这使得它能够使EOC细胞对化疗药物敏感，将提供关于化疗增敏剂的特征作用模式的有价值的信息。这将有助于识别新的药物和设计更好的联合治疗复发性卵巢癌患者的策略。
BACKGROUND. Previously, it was demonstrated that phenoxodiol induces apoptosis in epithelial ovarian carcinoma (EOC) cells and that it is capable of sensitizing these cells to Fas-mediated apoptosis. The objectives of this study were to determine whether phenoxodiol can also act as chemosensitizer to chemotherapeutic agents and to characterize the molecular mechanism behind its sensitizing effect.METHODS. Ten EOC cell lines were used in this study. The effect of phenoxodiol on the inhibitory concentration 50% (IC50) of carboplatin, paclitaxel, and gemcitabine was determined by the CellTiter 96 Assay. The in vivo effect of combination treatments with phenoxodiol and the above-mentioned agents was determined in animal xenograft models. Apoptosis was measured using the Caspase-Glo Assay and the apoptotic cascade was characterized by Western blot analyses.RESULTS. The results showed that phenoxodiol is able to sensitize EOC cells to carboplatin, paclitaxel, and gemcitabine both in vitro and in vivo. In addition, it was demonstrated that phenoxodiol is capable of inducing apoptosis by: 1) the activation of the mitochondrial pathway through caspase-2 and Bid signaling, and 2) the proteasomal degradation of the anti-apoptotic protein XIAP.CONCLUSION. Understanding the components of the apoptotic pathway activated by phenoxodiol, which allows it to sensitize EOC cells to chemotherapeutic agents, will provide valuable information on the characteristic mode of action of a chemosensitizer. This will help in the identification of novel drugs and in the design of better strategies for combination therapy in patients with recurrent ovarian carcinoma.