阿藿烯 B 通过抑制 P-糖蛋白和 NF-κB 信号通路逆转多柔比星耐药人骨肉瘤细胞系。
Alopecurone B reverses doxorubicin-resistant human osteosarcoma cell line by inhibiting P-glycoprotein and NF-kappa B signaling.
机构信息
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, NanJing 210009, People's Republic of China.
出版信息
Phytomedicine. 2015 Mar 15;22(3):344-51. doi: 10.1016/j.phymed.2014.12.011. Epub 2015 Jan 28.
Doxorubicin (DOX) was first used in osteosarcoma in the early 1970s as a first-line antineoplastic drug. However, the occurrence of drug resistance in chemotherapeutic treatment has greatly restricted its use. When resistance to DOX treatment occurs, osteosarcoma may become not only resistant to the drug originally administered but also to a wide variety of structurally and mechanistically unrelated drugs. Thus, there is an urgent need to find ways of reversing DOX chemotherapy resistance in osteosarcoma. Plant-derived agents have great potential in preventing the onset of the carcinogenic process and enhancing the efficacy of conventional antitumor drugs. Alopecurone B (ALOB), a flavonoid, is isolated from Traditional Chinese Medicine Sophora alopecuroides L., and is reported to have potent inhibitory effect on multidrug resistance associated protein 1. In this study, a DOX-resistant osteosarcoma cell line (MG-63/DOX) was established by increasing the concentration gradient of DOX in a stepwise manner. MTT assay, flow cytometry analysis, dual-luciferase reporter gene assay, quantitative real-time polymerase chain reaction and Western blot analysis were applied to investigate the reversing effect of ALOB and its underlying mechanisms. The results indicated that ALOB mediated the resistance of MG-63/DOX cells to DOX by inhibiting P-glycoprotein function, transcription and expression. Besides, ALOB also enhanced the sensitivity of MG-63/DOX cells to other conventional chemotherapeutic drugs. Cell viability assay confirmed the reversing activity of ALOB. Furthermore, ALOB increased DOX-induced apoptosis at nontoxic concentration. In addition, ALOB showed inhibitory effect on NF-κB transcription in a DOX-independent manner. Furthermore, NF-κB signaling was suppressed by ALOB in an IKK-dependent manner. These studies not only demonstrate that ALOB is a potential agent for reversal of drug resistant cancers, but also testify that ALOB reverses multidrug resistance by inhibiting P-glycoprotein via NF-κB signaling.
阿霉素（DOX）于 20 世纪 70 年代初首次被用于骨肉瘤的一线抗肿瘤药物。然而，化疗治疗中耐药性的发生极大地限制了其应用。当 DOX 治疗出现耐药性时，骨肉瘤不仅可能对最初给予的药物产生耐药性，而且还可能对广泛的结构和机制上无关的药物产生耐药性。因此，迫切需要寻找逆转骨肉瘤中 DOX 化疗耐药性的方法。植物来源的药物在预防致癌过程的发生和增强常规抗肿瘤药物的疗效方面具有巨大的潜力。阿藿烯 B（ALOB）是一种黄酮类化合物，从传统中药苦参中分离得到，据报道对多药耐药相关蛋白 1 具有很强的抑制作用。在这项研究中，通过逐步增加 DOX 的浓度梯度，建立了 DOX 耐药骨肉瘤细胞系（MG-63/DOX）。MTT 测定、流式细胞术分析、双荧光素酶报告基因测定、实时定量聚合酶链反应和 Western blot 分析用于研究 ALOB 的逆转作用及其潜在机制。结果表明，ALOB 通过抑制 P-糖蛋白的功能、转录和表达来介导 MG-63/DOX 细胞对 DOX 的耐药性。此外，ALOB 还增强了 MG-63/DOX 细胞对其他常规化疗药物的敏感性。细胞活力测定证实了 ALOB 的逆转活性。此外，ALOB 在无毒浓度下增加了 DOX 诱导的细胞凋亡。此外，ALOB 以 DOX 独立的方式对 NF-κB 转录具有抑制作用。此外，ALOB 通过 IKK 依赖性方式抑制 NF-κB 信号。这些研究不仅表明 ALOB 是逆转耐药性癌症的潜在药物，还证明 ALOB 通过 NF-κB 信号抑制 P-糖蛋白来逆转多药耐药性。
Zotero 插件