洛伐他汀或辛伐他汀协同组蛋白去乙酰化酶抑制剂对人非小细胞肺癌的抑制作用

Statins enhance anti-tumor effect of suberoylanilide hydroxamic acid on human non-small cell lung carcinoma cells

目的：研究他汀类药物能否协同增强组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸（SAHA）对非小细胞肺癌A549细胞的生长抑制和凋亡诱导作用。方法：采用磺酰罗丹明B比色法检测不同浓度的SAHA与洛伐他汀／辛伐他汀合用对A549细胞存活率的影响；采用Annexinv／PI双染结合流式细胞术检测2．5μmol／LSAHA与不同浓度的洛伐他汀联合应用对A549细胞凋亡的影响；并采用蛋白质印迹法检测2．5μmot／LSAHA与5μmol／L洛伐他汀联合作用对凋亡相关标志蛋白聚腺苷二磷酸核糖聚合酶（c-PARP）及p21蛋白表达水平影响。结果：与SAHA组比较，洛伐他汀／辛伐他汀与SAHA合用组减少A549细胞的存活率。不同浓度的洛伐他汀能协同增加SAHA对A549细胞的凋亡诱导作用，同时合用组c-PARP的表达较单用两组增加，说明洛伐他汀能协同SAHA诱导A549细胞凋亡。2．5μmol／LSAHA单独作用A549细胞48h可以上调A549细胞p21蛋白的表达，5μmol／L洛伐他汀与2．5μmol／LSAHA合用可以回调p21蛋白的表达。结论：洛伐他汀及辛伐他汀能增加SAHA对非小细胞肺癌A549细胞的生长抑制作用，其中洛伐他汀增强SAHA对A549细胞的生长抑制作用可能与其共同作用后p21蛋白表达下调相关。

Objective： To evaluate the anti-tumor effect of the combination of suberoylanilide hydroxamic acid （SAHA） with statins （lovastatin or simvastatin ） on non-small cell lung carcinoma （ NSCLC ） cells. Methods ： Human NSCLC A549 cells were treated with SAHA in combination of lovastatin or simvastatin. The cell growth was analyzed by SRB method, and the apoptosis of A549 cells was assessed by flow cytometer. The expression of cleaved poly-ADP-ribose polymerase （cleaved-PARP） and p21 protein was analyzed by Western-blotting when A549 cells were challenged with 2.5 μmol/L SAHA and 5 μmol/L lovastatin. Results： Lovastatin and simvastatin synergized SAHA in the inhibition of A549 cells. SAHA induced apoptosis was also enhanced by lovastatin. Treatment with 2.5 μmol/L SAHA significantly up-regulated the expression of p21 protein in 48 h, while the protein expression was reduced in combined treatment with 5 μmol/L lovastatin. Conclusion： Statins can synergize the anti-tumor effect of SAHA in human NSCLC cells through a p21-dependent way.