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Selective synergistic anticancer effects of cisplatin and oridonin against human p53-mutant esophageal squamous carcinoma cells.
Anti-Cancer Drugs ( IF 2.3 ) Pub Date : 2021-09-13 , DOI: 10.1097/cad.0000000000001237
Huiyu Yang 1, 2 , Jie Wang 2, 3 , Suliman Khan 4 , Yuanying Zhang 1, 2, 5 , Kuicheng Zhu 2, 5 , Enhui Zhou 2, 6 , Meiyuan Gong 2, 3 , Bingrong Liu 1, 2, 5 , Quancheng Kan 7 , Qi Zhang 1, 2, 3
Affiliation  

Oridonin (ORI) is known to pose anticancer activity against cancer, which could induce the therapeutic impact of chemotherapy drugs. However, such simple combinations have numerous side effects such as higher toxicity to normal cells and tissues. To enhance the therapeutic effects with minimal side effects, here we used ORI in combination with cisplitin (CIS) against different esophageal squamous cell carcinoma (ESCC) cell lines in vitro, to investigate the synergistic anticancer effects of the two drugs against ESCC. Calcusyn Graphing Software was used to assess the synergistic effect. Apoptosis, wound healing and cell invasion assay were conducted to further confirm the synergistic effects of ORI and CIS. Intracellular glutathione (GSH) and reactive oxygen species assay, immunofluorescence staining and western blot were used to verify the mechanism of synergistic cytotoxicity. ORI and CIS pose selective synergistic effects on ESCC cells with p53 mutations. Moreover, we found that the synergistic effects of these drugs are mediated by GSH/ROS systems, such that intracellular GSH production was inhibited, whereas the ROS generation was induced following ORI and CIS application. In addition, we noted that DNA damage was induced as in response to ORI and CIS treatment. Overall, these results suggest that ORI can synergistically enhance the effect of CIS, and GSH deficiency and p53 mutation, might be biomarkers for the combinational usage of ORI and CIS.

中文翻译:

顺铂和冬凌草甲素对人p53突变型食管鳞癌细胞的选择性协同抗癌作用。

冬凌草甲素 (ORI) 已知具有抗癌活性,可诱导化疗药物的治疗作用。然而,这种简单的组合具有许多副作用,例如对正常细胞和组织的毒性较高。为了以最小的副作用增强治疗效果,我们在体外使用ORI联合cisplitin(CIS)对抗不同的食管鳞状细胞癌(ESCC)细胞系,研究两种药物对抗ESCC的协同抗癌作用。Calcusyn 绘图软件用于评估协同效应。进行细胞凋亡、伤口愈合和细胞侵袭实验,以进一步证实ORI和CIS的协同作用。采用细胞内谷胱甘肽(GSH)和活性氧测定、免疫荧光染色和蛋白质印迹来验证协同细胞毒性的机制。ORI 和 CIS 对 p53 突变的 ESCC 细胞产生选择性协同作用。此外,我们发现这些药物的协同作用是由 GSH/ROS 系统介导的,因此细胞内 GSH 的产生受到抑制,而 ORI 和 CIS 的应用则诱导 ROS 的产生。此外,我们注意到 ORI 和 CIS 治疗会诱导 DNA 损伤。总的来说,这些结果表明ORI可以协同增强CIS的效果,GSH缺乏和p53突变可能是ORI和CIS联合使用的生物标志物。
更新日期:2021-09-13
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