Wogonin exacerbates the cytotoxic effect of oxaliplatin by inducing nitrosative stress and autophagy in human gastric cancer cells
Wogonin exacerbates the cytotoxic effect of oxaliplatin by inducing nitrosative stress and autophagy in human gastric cancer cells
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汉黄芩素通过诱导人胃癌细胞亚硝化应激和自噬而加剧奥沙利铂的细胞毒作用
DOI：
10.1016/j.phymed.2017.12.019
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发表时间：
2018-01-15
期刊：
影响因子：
7.9
通讯作者：
Wang, Xue-Zhi
中科院分区：
文献类型：
--
作者：
Hong, Zhi-Pan;Wang, Li-Guo;Wang, Xue-Zhi
背景：胃癌仍然是世界上最主要的死亡原因之一。目的：研究汉黄连甲素联合奥沙利铂在体内外对胃癌细胞的药理作用。方法与结果：在本研究中，我们发现汉黄连甲素增强了奥沙利铂的细胞毒作用；在BGC-823细胞和斑马鱼异种移植模型中，联合用药对细胞活力有很强的协同抑制作用。有趣的是，汉黄连甲素和奥沙利铂联合处理可调节磷酸化JNK(Thr183/Tyr185)和磷酸化ULK1(Ser555)的表达，并形成LC3II。共聚焦成像数据一致显示，汉黄连甲素加剧了奥沙利铂诱导的BGC-823细胞线粒体膜电位(Delta Psi M)的耗散和过氧亚硝酸根的形成。此外，汉黄连甲素与奥沙利铂合用可减少奥沙利铂的剂量，因此，在取得相同疗效的同时减少奥沙利铂的副作用是一种相关的策略。结论：汉黄连甲素有可能成为提高奥沙利铂治疗胃癌疗效的潜在候选药物。
Background: Gastric cancer remains one of the leading cause of death in the world. Drug combinations are potential approaches to provide more efficient treatments that minimize side effects.Purpose: We investigated the pharmacological effects of the combination of wogonin with oxaliplatin on gastric cancer cells in vitro and in vivo.Methods and Results: In the present study, we found that wogonin enhanced the cytotoxicity of oxaliplatin; the drug combination resulted in strong synergistic inhibition of the cell viability in BGC-823 cells and in a zebrafish xenograft model. Interestingly, the combined treatment of wogonin and oxaliplatin modulated the expression of phospho-JNK (Thr183/Tyr185), phospho-ULK1 (Ser555) and the formation of LC3II. Confocal imaging data consistently showed that wogonin exacerbates the oxaliplatin-induced dissipation of the mitochondrial membrane potential (Delta Psi m) and formation of peroxynitrite in BGC-823 cells. Moreover, wogonin allows a reduction in oxaliplatin dose when they are combined; therefore, it is a relevant strategy for reducing the side effects of oxaliplatin while achieving the same response.Conclusion: These results suggest that wogonin can be a potential therapeutic candidate for enhancing the efficacy of oxaliplatin in gastric cancer treatment.