Berberine combined with 2-deoxy-D-glucose synergistically enhances cancer cell proliferation inhibition via energy depletion and unfolded protein response disruption
Berberine combined with 2-deoxy-D-glucose synergistically enhances cancer cell proliferation inhibition via energy depletion and unfolded protein response disruption
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小檗碱与 2-脱氧-d-葡萄糖结合通过能量消耗和未折叠蛋白反应破坏协同增强癌细胞增殖抑制
DOI：
10.1016/j.bbagen.2013.07.010
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发表时间：
2013-11-01
影响因子：
3
通讯作者：
Li, Jia
中科院分区：
文献类型：
--
作者：
Fan, Li-xia;Liu, Chang-mei;Li, Jia
工作背景：靶向细胞代谢的多个方面，例如有氧糖酵解和线粒体氧化磷酸化（OXPHOS），具有改善癌症治疗的潜力。小檗碱（Berberine，BBR）是一种广泛应用的中药，通过抑制OXPHOS而发挥抗肿瘤作用。2-脱氧-n-葡萄糖（2-DG）靶向有氧糖酵解，并在临床上显示出潜在的抗癌作用。我们假设，BBR与2-DG的组合将是更有效的比任何单独的代理对癌细胞growth.Methods：BBR和2-DG对癌细胞生长的影响进行了评估，使用磺酰罗丹明B（SR B）的方法。PI摄取试验检测细胞死亡，Western印迹、Q-PCR和荧光素酶报告基因试验用于信号通路检测。使用腺病毒系统进行基因过表达。结果：BBR与2-DG联合应用对体外培养的肿瘤细胞有协同抑制作用。进一步的机制研究表明，该组合大大增强了ATP消耗，并强烈破坏了未折叠蛋白反应（UPR）。过表达GRP 78部分地阻止了两种化合物诱导的癌细胞抑制。结论：在这里，我们首次报道了BBR和2-DG对与ATP能量消耗和UPR破坏相关的癌细胞生长抑制具有协同作用。我们的研究结果提出了BBR和2-DG联合作为抗癌治疗的潜在用途，强化了靶向有氧糖酵解和OXPHOS提供更有效的癌症治疗的假设，并突出了UPR在该过程中的重要作用。(C)2013 Elsevier B. V.保留所有权利。
Background: Targeting multiple aspects of cellular metabolism, such as both aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), has the potential to improve cancer therapeutics. Berberine (BBR), a widely used traditional Chinese medicine, exerts its antitumor effects by inhibiting OXPHOS. 2-Deoxy-n-glucose (2-DG) targets aerobic glycolysis and demonstrates potential anticancer effects in the clinic. We hypothesized that BBR in combination with 2-DG would be more efficient than either agent alone against cancer cell growth.Methods: The effects of BBR and 2-DG on cancer cell growth were evaluated using the Sulforhodamine B (SRB) method. Cell death was detected with the PI uptake assay, and Western blot, Q-PCR and luciferase reporter assays were used for signaling pathway detection. An adenovirus system was used for gene overexpression. Results: BBR combined with 2-DG synergistically enhanced the growth inhibition of cancer cells in vitro. Further mechanistic studies showed that the combination drastically enhanced ATP depletion and strongly disrupted the unfolded protein response (UPR). Overexpressing GRP78 partially prevented the cancer cell inhibition induced by both compounds.Conclusions: Here, we report for the first time that BBR and 2-DG have a synergistic effect on cancer cell growth inhibition related to ATP energy depletion and disruption of UPR.General significance: Our results propose the potential use of BBR and 2-DG in combination as an anticancer treatment, reinforcing the hypothesis that targeting both aerobic glycolysis and OXPHOS provides more effective cancer therapy and highlighting the important role of UPR in the process. (C) 2013 Elsevier B.V. All rights reserved.