Wang Ying, Yuan Shoujun, Li Linna, Yang Dexuan, Xu Chengwang, Wang Shanshan, Zhang Danshen
Department of Pharmacology, School of Pharmacy, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Oncol Lett. 2017 Jun;13(6):4762-4768. doi: 10.3892/ol.2017.6043. Epub 2017 Apr 19.
5-Fluorouracil (5-FU) is one of the most important agents used to treat colorectal cancer. However, the therapeutic effect of 5-FU on colon cancer is limited. SM-1 is a novel type of proapoptotic agent that directly activates procaspase-3 to caspase-3, leading to apoptosis in human cancer cells. The aim of the present study was to evaluate the antitumor effects of 5-FU in combination with SM-1. The human colorectal cancer cell lines HCT116 and LoVo were cultured in the presence of SM-1 and 5-FU. The combination of SM-1 and 5-FU treatment exhibited increased proliferation inhibitory effects compared with 5-FU treatment alone in HCT116 and LoVo cells, as determined using an MTT assay. SM-1 significantly decreased the half-maximal inhibitory concentration of 5-FU from 8.07±0.49 to 2.55±0.41 µmol/l in HCT116 cells, and from 7.90±0.98 to 3.14±0.81 µmol/l in LoVo cells. Similarly, the apoptotic activity was increased to 47.95 and 35.19% in HCT116 and LoVo cells, respectively, as determined using Annexin V/propidium iodide staining and flow cytometry. The combination of SM-1 and 5-FU treatment led to significantly increased caspase-3 activity compared with either compound alone. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis revealed the downregulation of B-cell lymphoma 2 and Survivin, and the upregulation of apoptosis regulator Bcl-2-associated X protein and cleaved poly (ADP-ribose) polymerase in HCT116 and LoVo cells. In addition, RT-qPCR identified downregulation of X-linked inhibitor of apoptosis protein mRNA. 5-FU and SM-1 treatment in combination increased tumor proliferation inhibition in HCT116 and LoVo xenograft mouse models of colorectal cancer, compared with SM-1 or 5-FU treatment alone. SM-1 significantly enhanced the antitumor activity of 5-FU in colorectal cancer. These improved effects were due to increased activity of the apoptotic signaling pathway.
5-氟尿嘧啶（5-FU）是用于治疗结直肠癌的最重要药物之一。然而，5-FU对结肠癌的治疗效果有限。SM-1是一种新型促凋亡剂，可直接将procaspase-3激活为caspase-3，从而导致人癌细胞凋亡。本研究的目的是评估5-FU与SM-1联合使用的抗肿瘤效果。将人结肠癌细胞系HCT116和LoVo在SM-1和5-FU存在的情况下进行培养。如通过MTT法所测定，与单独使用5-FU处理相比，SM-1与5-FU联合处理在HCT116和LoVo细胞中表现出增强的增殖抑制作用。在HCT116细胞中，SM-1显著将5-FU的半数最大抑制浓度从8.07±0.49 μmol/l降至2.55±0.41 μmol/l，在LoVo细胞中从7.90±0.98 μmol/l降至3.14±0.81 μmol/l。同样，如通过膜联蛋白V/碘化丙啶染色和流式细胞术所测定，在HCT116和LoVo细胞中，凋亡活性分别增加至47.95%和35.19%。与单独使用任一化合物相比，SM-1与5-FU联合处理导致caspase-3活性显著增加。逆转录-定量聚合酶链反应（RT-qPCR）和蛋白质印迹分析显示，在HCT116和LoVo细胞中，B细胞淋巴瘤2和生存素下调，凋亡调节因子Bcl-2相关X蛋白和裂解的聚（ADP-核糖）聚合酶上调。此外，RT-qPCR鉴定出X连锁凋亡抑制蛋白mRNA下调。与单独使用SM-1或5-FU处理相比，5-FU与SM-1联合处理在HCT116和LoVo人结直肠癌异种移植小鼠模型中增加了肿瘤增殖抑制。SM-1显著增强了5-FU在结直肠癌中的抗肿瘤活性。这些改善的效果归因于凋亡信号通路活性的增加。
