PDF(Pubmed)
Abstract：
BACKGROUND: Cancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative.
OBJECTIVE: In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.
METHODS: An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.
METHODS: We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.
RESULTS: The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).
CONCLUSIONS: Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.
OBJECTIVE: In this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.
METHODS: An integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.
METHODS: We applied a systems-based analysis to introduce a drug-target-pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.
RESULTS: The mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).
CONCLUSIONS: Our data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.
摘要：
背景：癌症是一种严重影响人类的致命疾病。设计新的抗癌策略和了解抗癌剂的作用机制势在必行。
目的：在本研究中，我们评估了二甲双胍和D-柠檬烯的效用，单独或组合，作为使用人肝癌和乳腺癌细胞系HepG2和MCF-7的潜在抗癌疗法。
方法：提出了一种集成系统药理学方法，用于说明二甲双胍和D-柠檬烯之间的分子相互作用。
方法：我们应用了基于系统的分析，引入了药物-靶标-途径网络，阐明了不同的治疗机制。与单一药物治疗相比，二甲双胍和D-柠檬烯联合治疗可诱导两种细胞系的细胞凋亡。如流式细胞仪和基因表达分析所示。
结果：Bax和P53基因的mRNA表达明显上调，而Bcl-2、iNOS、与正常细胞相比,所有治疗组的Cox-2显著下调。晚期凋亡HepG2和MCF-7细胞的百分比在所有治疗组中均较高。特别是在联合治疗组中。组合指数(CI)的计算揭示了两种药物对于HepG2细胞(CI=0.14)和MCF-7细胞(CI=0.22)之间的协同作用。
结论：我们的数据显示二甲双胍，D-柠檬烯,它们的组合通过诱导凋亡和调节凋亡基因的表达对癌细胞系具有显著的抗肿瘤作用。
目的：在本研究中，我们评估了二甲双胍和D-柠檬烯的效用，单独或组合，作为使用人肝癌和乳腺癌细胞系HepG2和MCF-7的潜在抗癌疗法。
方法：提出了一种集成系统药理学方法，用于说明二甲双胍和D-柠檬烯之间的分子相互作用。
方法：我们应用了基于系统的分析，引入了药物-靶标-途径网络，阐明了不同的治疗机制。与单一药物治疗相比，二甲双胍和D-柠檬烯联合治疗可诱导两种细胞系的细胞凋亡。如流式细胞仪和基因表达分析所示。
结果：Bax和P53基因的mRNA表达明显上调，而Bcl-2、iNOS、与正常细胞相比,所有治疗组的Cox-2显著下调。晚期凋亡HepG2和MCF-7细胞的百分比在所有治疗组中均较高。特别是在联合治疗组中。组合指数(CI)的计算揭示了两种药物对于HepG2细胞(CI=0.14)和MCF-7细胞(CI=0.22)之间的协同作用。
结论：我们的数据显示二甲双胍，D-柠檬烯,它们的组合通过诱导凋亡和调节凋亡基因的表达对癌细胞系具有显著的抗肿瘤作用。
