The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines
The effects of metformin and simvastatin on the growth of LNCaP and RWPE-1 prostate epithelial cell lines
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DOI：
10.1016/j.ejphar.2016.06.036
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发表时间：
2016-10-05
影响因子：
5
通讯作者：
Murtola, Teemu J.
中科院分区：
文献类型：
--
作者：
Pennanen, Pasi;Syvala, Heimo;Murtola, Teemu J.
抗糖尿病药物二甲双胍和降胆固醇他汀类药物在体外抑制前列腺癌细胞生长，并在流行病学研究中与降低前列腺癌风险有关。我们评估了这些药物对癌性和非癌性前列腺上皮细胞系的影响。癌症（LNCaP）和正常（RWPE- 1）前列腺上皮细胞系用药理学浓度的二甲双胍和辛伐他汀单独和组合处理。结晶紫染色法测定细胞数量的相对变化。流式细胞仪检测药物对细胞凋亡和细胞周期的影响。我们还测量了一组报告的二甲双胍和他汀类药物的靶蛋白的激活和表达的变化与蛋白质印迹法。二甲双胍通过诱导G1期细胞周期阻滞、自噬和凋亡减少LNCaP细胞的相对细胞数，并轻微增加胞浆ATP水平，而RWPE- 1细胞对二甲双胍耐药。然而，RWPE- 1细胞对辛伐他汀敏感，辛伐他汀诱导G2期细胞周期阻滞、自噬和凋亡，并增加这些细胞中胞浆ATP水平。二甲双胍和辛伐他汀的组合协同降低细胞溶质ATP水平，增加自噬，而不是凋亡，诱导LNCaP细胞坏死。在RWPE-1细胞中未观察到协同作用。这些结果表明，与正常细胞相比，前列腺癌细胞可能更容易受到二甲双胍和辛伐他汀的联合生长抑制作用的影响。本文提供的数据为二甲双胍和他汀类药物联合治疗（也是在药理学浓度下）作为前列腺癌化疗选择的效力提供了证据。(C)2016爱思唯尔B. V.保留所有权利。
The anti-diabetic drug metformin and cholesterol-lowering statins inhibit prostate cancer cell growth in vitro and have been linked with lowered risk of prostate cancer in epidemiological studies. We evaluated the effects of these drugs on cancerous and non-cancerous prostate epithelial cell lines. Cancer (LNCaP) and normal (RWPE- 1) prostate epithelial cell lines were treated with pharmacologic concentrations of metformin and simvastatin alone and in combinations. Relative changes in cell number were measured with crystal violet staining method. Drug effects on apoptosis and cell cycle were measured with flow cytometry. We also measured changes in the activation and expression of a set of reported target proteins of metformin and statins with Western blotting. Metformin decreased the relative cell number of LNCaP cells by inducing G1 cell cycle block, autophagy and apoptosis, and slightly increased cytosolic ATP levels, whereas RWPE- 1 cells were resistant to metformin. However, RWPE- 1 cells were sensitive to simvastatin, which induced G2 cell cycle block, autophagy and apoptosis, and increased cytosolic ATP levels in these cells. Combination of metformin and simvastatin synergistically decreased cytosolic ATP levels, increased autophagy and instead of apoptosis, induced necrosis in LNCaP cells. Synergistic effects were not observed in RWPE- 1cells. These results suggest, that prostate cancer cells may be more vulnerable to combined growth-inhibiting effects of metformin and simvastatin compared to normal cells. The data presented here provide evidence for the potency of combined metformin and statin, also at pharmacologic concentrations, as a chemotherapeutic option for prostate cancer. (C) 2016 Elsevier B.V. All rights reserved.