Department of Molecular Medicine, Laval University, Québec, Canada.
FEBS J. 2010 Dec;277(24):5146-60. doi: 10.1111/j.1742-4658.2010.07928.x. Epub 2010 Nov 16.
The standard chemotherapy for epithelial ovarian cancer (EOC) patients is currently a combination of taxane and platinum. However, most EOC patients still suffer relapses, and there is an immediate need for the development of novel and more effective therapeutic modalities against this deadly disease. Recently, the nonpeptide bradykinin (BK) antagonist 2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-l-tyrosine-N-(4-amino-2,2,6,6-tetramethyl-piperidyl) amide (BKM-570) was shown to cause impressive growth inhibition of lung and prostate tumors, displaying superior in vivo inhibitory effects than convential chemotherapeutic drugs. Here, we investigated BKM-570 cytotoxic effects in two EOC cell lines, derived from different EOC histopathologies: a clear cell carcinoma (TOV-21), and an endometrioid carcinoma (TOV-112). We showed that BKM-570 effectively inhibited the growth of ovarian cancer cells, as its cytotoxic effects were comparable to those of cisplatin, and were independent of the functional status of BK receptors. Moreover, BKM-570 synergized with cisplatin in inhibiting EOC cell growth. To better understand the molecular mechanisms of the antiproliferative action of this BK antagonist in EOC cells, we performed gene expression profiling in TOV-21 and TOV-112 cells following treatment with 10 μM BKM-570 for 24 h. BKM-570 displayed similar cytotoxic effects in the two cell lines analyzed, as genes with previously shown involvement in apoptosis/antiapoptosis and cell adhesion were proportionally upregulated and downregulated in both cell lines, whereas genes involved in basic cellular mechanisms, including cell growth and maintenance, metabolism, cell cycle control, inflammatory and immune response, signal transduction, protein biosynthesis, transcription regulation, and transport, were predominantly downregulated upon treatment. Our data are indicative of the therapeutic potential of BKM-570 and related compounds in EOC management.
上皮性卵巢癌（EOC）患者的标准化疗目前是紫杉醇和铂类药物的联合应用。然而，大多数 EOC 患者仍会复发，因此迫切需要开发针对这种致命疾病的新型、更有效的治疗方法。最近，非肽类缓激肽（BK）拮抗剂 2,3,4,5,6-五氟肉桂酰基-（邻-2,6-二氯苄基）-L-酪氨酸-N-（4-氨基-2,2,6,6-四甲基-哌啶基）酰胺（BKM-570）被证明可显著抑制肺和前列腺肿瘤的生长，其体内抑制作用优于传统化疗药物。在这里，我们研究了 BKM-570 在两种源自不同 EOC 组织病理学的 EOC 细胞系中的细胞毒性作用：一种透明细胞癌（TOV-21）和一种子宫内膜样癌（TOV-112）。我们表明，BKM-570 有效抑制卵巢癌细胞的生长，其细胞毒性作用与顺铂相当，并且与 BK 受体的功能状态无关。此外，BKM-570 与顺铂协同抑制 EOC 细胞生长。为了更好地理解这种 BK 拮抗剂在 EOC 细胞中抗增殖作用的分子机制，我们在 TOV-21 和 TOV-112 细胞中用 10 μM BKM-570 处理 24 小时后进行了基因表达谱分析。BKM-570 在两种分析的细胞系中表现出相似的细胞毒性作用，因为先前显示参与凋亡/抗凋亡和细胞黏附的基因在两种细胞系中按比例上调和下调，而参与基本细胞机制的基因，包括细胞生长和维持、代谢、细胞周期控制、炎症和免疫反应、信号转导、蛋白质生物合成、转录调节和运输，在治疗后主要下调。我们的数据表明 BKM-570 及其相关化合物在 EOC 治疗中的治疗潜力。
