唑来膦酸对肺腺癌细胞的生长及化疗敏感性研究

Effects of zoledronic acid on growth of human lung adenocarcinoma cell line A549 in vitro

目的:本研究主要探讨第三代双磷酸盐类药物唑来膦酸在体外对人肺腺癌细胞株A549生长的影响,进一步研究唑来膦酸与顺铂(DDP)对A549细胞的生长抑制是否具有协同作用。方法:采用MTT法检测不同剂量的唑来膦酸对人肺癌细胞株A549的生长作用,检测唑来膦酸单药及联合DDP对人肺腺癌细胞A549的增殖抑制,采用流式细胞术分析唑来膦酸联合DDP对细胞周期及凋亡的影响。结果:唑来膦酸对A549细胞的抑制效应与药物剂量及作用时间均成正比。单用唑来膦酸(1、10μmol/L)对A549细胞的生长抑制率分别为(20.69±2.69)%、(44.05±4.03)%,单用DDP(0.5mg/L)组的抑制率为(13.58±3.13)%。唑来膦酸(1、10μmol/L)联合DDP(0.5mg/L)作用A549细胞72h时,对A549细胞的生长抑制率分别为(44.23±3.77)%、(60.9±3.03)%,联合用药组与单药组相比差异有显著性(P<0.01)。唑来膦酸作用A549细胞72h的IC50值为25μmol/L。流式细胞术分析显示,单用唑来膦酸(1、10μmol/L)的细胞凋亡率分别为(16.94±1.95)%、(24.03±0.44)%,单用DDP(0.5mg/L)组的细胞凋亡率为(9.08±1.31)%。唑来膦酸(1、10μmol/L)联合DDP(0.5mg/L)时,引起的细胞凋亡率分别为(32.22±1.68)%、(39.22±7.00)%,联合用药组的凋亡率明显高于单药组(P<0.01)。唑来膦酸单药或者联合DDP均表现将A549细胞明显阻滞于S期(DNA合成期)。结论:唑来膦酸对肺癌细胞株有生长抑制作用,呈时间、剂量依赖性效应,其IC50值为25μmol/L。唑来膦酸可以干扰DNA合成,与DDP有协同作用。

Objective： To evaluate the effects of zoledronic acid on growth of human lung adenocarcinoma cell line A549, and to investigate whether this effect was mediated by induction of cell cycle arrest or apoptosis and whether there was a synergistic interaction between zoledronic acid and cisplatin. Methods： Zoledronic acid alone or combined with anticancer drug cisplatin were used to treat human lung adenocarcinoma A549 cell line. The cell growth inhibition and cell cycle apoptosis were assessed by MTr and flow cytometry. Results： There was a dose-dependent and time-dependent （1～200 μmol/L） inhibition of cell proliferation by zoledronic acid. IC50 value of zoledronic acid for therapy of A549 after 72 h was 25μmol/L. The cell growth inhibition rate of A549 after 72 h was（13.58 ±3.13）% in cisplatin（0.5 mg/L）group, and （20.69± 2.69）% and （44.05 ± 4.03）% in zoledronic acid groups （1 μmol/ L, 10μmol]L）. When combined treatment of zoledronic acid （1μmol/L, 10 μmol/L） and cisplatin （0.5 mg/L）was used, the cell growth inhibition rates were （44.23 ± 3.77）% and （60.9 ± 3.03）%, respectively. These differences were significant （P 〈 0. 01 ）. The apoptotic rate of A549 cells induced by cisplatin（0.5 mg/L）was（9.08 ± 1.31）%, and that induced by zoledronic acid （1μmol/L, 10 μmol/L） was （16.94 ± 1.95）% and （24.03 ± 0.44）%, respectively. The apoptotic rate was （32.22± 1.68）% or （39.22±7.00）% after combined treatment of zoledronic acid （1μmol/L or 10μmol/L） and cisplatin （0.5 mg/L）. Conclusion： Zoledronic acid has an explicit effect of inhibiting proliferation of A549 cells in a time- and dose-dependent manner. Its IC5o value is 25μmol/L. Zoledronic acid could induce apoptosis, and has a synergistic interaction with cisplatin.