Piperlongumine通过ROS诱导增强奥沙利铂对癌症细胞的抗肿瘤作用

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2019-12-01 Epub Date: 2019-09-06 DOI:10.1007/s13402-019-00471-x
Peichen Zhang, Lingyan Shi, Tingting Zhang, Lin Hong, Wei He, Peihai Cao, Xin Shen, Peisen Zheng, Yiqun Xia, Peng Zou
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引用次数: 40

摘要

目的:奥沙利铂是治疗包括胃癌在内的各种癌症最常用的化疗药物之一。然而,由于其毒性和耐药性的出现,它的治疗指数较窄。因此,迫切需要开发新型疗法来增强奥沙利铂的疗效并降低其毒性。胡椒龙葵碱(Piperlongumine,PL)是从胡椒龙葵(Piper longum L.)中分离出来的一种生物碱,最近被确认为体外和体内抗癌细胞的有效药物。在本研究中,我们探讨了PL能否增强奥沙利铂对胃癌细胞的抗肿瘤作用:方法:采用流式细胞术分析细胞凋亡和 ROS 水平。采用终点胰岛素还原试验测定胃癌细胞或肿瘤组织中硫氧还原酶 1 (TrxR1) 的活性。用 Western 印迹法分析所述蛋白质的表达水平。裸鼠异种移植模型用于检测 PL 和奥沙利铂组合对胃癌细胞体内生长的影响:结果:我们发现 PL 能明显增强奥沙利铂诱导的胃癌和结肠癌细胞的生长抑制作用。此外,我们还发现 PL 通过抑制 TrxR1 的活性增强了奥沙利铂的抗肿瘤作用。PL与奥沙利铂联合使用可明显抑制TrxR1的活性,导致ROS积累,从而诱发DNA损伤,激活p38和JNK信号通路。使用抗氧化剂 N-乙酰-L-半胱氨酸(NAC)进行预处理可显著减少联合治疗诱导的 ROS 生成、DNA 损伤和细胞凋亡。重要的是,我们发现 NAC 预处理还能逆转 PL 和奥沙利铂对 p38 和 JNK 信号通路的激活。在体内,我们发现 PL 联合奥沙利铂能显著抑制胃癌异种移植模型中的肿瘤生长,并有效降低肿瘤组织中 TrxR1 的活性。值得注意的是,我们发现 PL 能减轻奥沙利铂治疗引起的体重下降:我们的数据支持 PL 和奥沙利铂的协同作用,并表明联合应用 PL 和奥沙利铂治疗胃癌可能比单独应用奥沙利铂更有效。
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Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells.

Purpose: Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells.

Methods: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo.

Results: We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment.

Conclusions: Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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