Zhao Xiao-Yan, Yang Shen, Chen You-Ran, Li Pei-Chun, Dou Meng-Meng, Zhang Jie
College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
Department of Neurology, The Ninth People's Hospital of Chongqing, Chongqing, China.
PLoS One. 2014 Jun 5;9(6):e98925. doi: 10.1371/journal.pone.0098925. eCollection 2014.
Arsenic trioxide (As2O3), which used as an effective agent in the treatment of leukaemia and other solid tumors, is largely limited by its toxicity. QT prolongation, torsades de pointes and sudden heart death have been implicated in the cardiotoxicity of As2O3. The present study was designed to explore whether the combination of As2O3 and resveratrol could generate a more powerful anti-cancer effect both in vitro and in vivo.
MTT assay was performed to assess the proliferation of Hela, MCF-7 and NB4 cells. Isobolographic analysis was used to evaluate combination index values from cell viability data. The apoptosis and the cellular reactive oxygen species (ROS) level were assessed by fluorescent microscopy and flow cytometry separately in vitro. The effect of As2O3, alone and in combination with resveratrol on Hela tumor growth in an orthotopic nude mouse model was also investigated. The tumor volume and the immunohistochemical analysis of CD31, CD34 and VEGF were determined.
Resveratrol dramatically enhanced the anti-cancer effect induced by As2O3 in vitro. In addition, isobolographic analysis further demonstrated that As2O3 and resveratrol generated a synergistic action. More apoptosis and ROS generation were observed in the combination treatment group. Similar synergistic effects were found in nude mice in vivo. The combination of As2O3 and resveratrol dramatically suppressed both tumor growth and angiogenesis in nude mice.
Combining As2O3 with resveratrol would be a novel strategy to treat cancer in clinical practice.
三氧化二砷（As2O3）作为治疗白血病和其他实体瘤的有效药物，其应用在很大程度上受到毒性的限制。QT间期延长、尖端扭转型室速和心脏性猝死与As2O3的心脏毒性有关。本研究旨在探讨As2O3与白藜芦醇联合使用是否能在体外和体内产生更强的抗癌效果。
采用MTT法评估Hela、MCF-7和NB4细胞的增殖情况。用等效线图分析法根据细胞活力数据评估联合指数值。分别通过荧光显微镜和流式细胞术在体外评估细胞凋亡和细胞活性氧（ROS）水平。还研究了As2O3单独及与白藜芦醇联合对原位裸鼠模型中Hela肿瘤生长的影响。测定肿瘤体积并对CD31、CD34和VEGF进行免疫组化分析。
白藜芦醇在体外显著增强了As2O3诱导的抗癌效果。此外，等效线图分析进一步表明As2O3和白藜芦醇产生了协同作用。联合治疗组观察到更多的细胞凋亡和ROS产生。在体内裸鼠中也发现了类似的协同作用。As2O3与白藜芦醇联合显著抑制了裸鼠的肿瘤生长和血管生成。
As2O3与白藜芦醇联合将是临床实践中治疗癌症的一种新策略。
