Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.
Biomed Res Int. 2013;2013:237543. doi: 10.1155/2013/237543. Epub 2013 Nov 10.
Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationale for combination therapy in successful treatment of lung cancer. Concurrent use of cyclooxygenase (COX) inhibitors with arsenic trioxide (ATO) might be a possible treatment option.
Cytotoxicity of ATO, dexamethasone (Dex), celecoxib (Cel), and Indomethacin (Indo) individually or in combination was determined at 24, 48, and 72 hrs in A549 lung cancer cells. The COX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations.
The IC50s of ATO and Indo were 68.7 μmol/L and 396.5 μmol/L, respectively. Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone. Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use. Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs.
Combination therapy with ATO and Indo exerted a very potent in vitro cytotoxic effect against A549 lung cancer cells. Activation of ERK and p38 pathways might be the mechanism of higher cytotoxic effect of ATO-Indo combination.
针对不同途径，特别是凋亡和 MAPK 的新型药物联合治疗可能是成功治疗肺癌的联合治疗的合理依据。同时使用环氧化酶 (COX) 抑制剂与三氧化二砷 (ATO) 可能是一种可行的治疗选择。
在 A549 肺癌细胞中，分别在 24、48 和 72 小时测定 ATO、地塞米松 (Dex)、塞来昔布 (Cel) 和吲哚美辛 (Indo) 单独或联合使用的细胞毒性。研究 COX-2 基因和蛋白表达、MAPK 通路蛋白和 caspase-3 活性，以确定最具细胞毒性的组合。
ATO 和 Indo 的 IC50 分别为 68.7 μmol/L 和 396.5 μmol/L。用临床相关浓度的 ATO 和 Indo 联合治疗细胞，比单独使用任何一种药物都能更有效地抑制生长和诱导凋亡。在存在 ATO 和 Indo 的情况下，caspase-3 活性明显升高，但在单独或联合使用时无差异。两种药物同时存在时，p38 和 ERK1/2 的磷酸化非常显著。
ATO 和 Indo 的联合治疗对 A549 肺癌细胞具有很强的体外细胞毒性作用。ERK 和 p38 通路的激活可能是 ATO-Indo 联合治疗具有更高细胞毒性作用的机制。
