Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer
Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer
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DOI：
10.1016/j.ygyno.2016.06.005
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发表时间：
2016-08-01
影响因子：
4.7
通讯作者：
Rattan, R.
中科院分区：
文献类型：
--
作者：
Hijaz, M.;Chhina, J.;Rattan, R.
目标。BRCA突变的卵巢癌对PARP抑制剂的反应性增强。PARP抑制剂的目标是DNA修复，并对BRCA突变的肿瘤提供第二次打击，导致“合成致命性”。我们研究了二甲双胍和奥拉帕利布的组合在BRCA完整的卵巢癌细胞中提供“合成杀伤力”。用二甲双胍和奥拉帕利布联合作用于卵巢癌细胞株UWB1.289、UWB1.289、BRCA、SKOV3、OVCAR5、A2780和C200。用四甲基偶氮唑盐比色法和集落形成实验检测细胞存活率。流式细胞仪检测细胞周期事件。在裸鼠体内进行了SKOV3或A2780移植瘤的研究。动物分别用单一药物、二甲双胍、奥拉帕利布或联合用药。用免疫组织化学方法检测分子下游效应。与单独用药相比，奥拉帕利布和二甲双胍联合用药可显著抑制卵巢癌细胞的增殖和集落形成(p<；0.001)。这种治疗与显著的S期细胞周期停滞有关(p<；0.05)。奥拉帕利布与二甲双胍联合应用可显著抑制卵巢癌裸鼠移植瘤和A2780卵巢癌移植瘤的生长，并伴有Ki指数下降(p<；0.001)。二甲双胍不影响DNA损伤信号转导，而奥拉帕利布可诱导腺苷一磷酸激活的激酶激活，联合应用可进一步增强DNA损伤信号转导作用。PARP抑制剂与二甲双胍联合使用可增强其在BRCA突变卵巢癌细胞中的抗增殖活性。此外，该组合在体外和体内对BRCA完整的癌细胞显示出显著的活性。对于患有上皮性卵巢癌的妇女来说，这是一种很有希望的治疗方案，无论BRCA状态如何。(C)2016 Elsevier Inc.保留所有权利。
Objectives. BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells.Methods. Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry.Results. Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p < 0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p < 0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p < 0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo.Conclusion. Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status. (C) 2016 Elsevier Inc. All rights reserved.