双靶点药物NL-101的抗多发性骨髓瘤活性及其机制研究

发布时间：2018-05-19 09:50

本文选题：NL- + DNA损伤　；参考：《中国药科大学学报》2017年04期

【摘要】：研究具有组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制和DNA损伤双靶点化合物NL-101的体内外抗多发性骨髓瘤活性及其机制研究。在10株多发性骨髓瘤细胞株中,采用CTG法检测化合物NL-101对肿瘤细胞增殖的影响以及在RPMI 8226细胞中NL-101与硼替佐米的联用效果,采用流式细胞仪检测NL-101对细胞周期的影响,Western blot检测NL-101对乙酰化组蛋白H3、乙酰化α-Tubulin和磷酸化Histone H2A.X的表达影响,并在RPMI 8226多发性骨髓瘤细胞皮下移植瘤模型中考察NL-101单用以及与硼替佐米联用的抑瘤效果。研究结果表明,NL-101能同时产生HDAC抑制剂和DNA烷化剂双重活性,不但抑制肿瘤细胞组蛋白去乙酰化水平,而且增加DNA损伤,最终诱导细胞周期阻滞和细胞凋亡。在细胞水平和动物移植瘤模型中均表现出较强的抗肿瘤活性,优于阳性对照药美法仑,而且与硼替佐米联用具有协同增效作用。NL-101有望成为一个全新的抗多发性骨髓瘤药物。
[Abstract]:To study the anti-multiple myeloma activity in vitro and in vivo of NL-101, a double target compound with histone deacetylase (HDAC) and DNA damage. In 10 multiple myeloma cell lines, CTG assay was used to detect the effect of compound NL-101 on the proliferation of tumor cells and the combined use of NL-101 and bortezomil in RPMI 8226 cells. The effect of NL-101 on cell cycle was detected by flow cytometry and the expression of acetylated histone H3, acetylated 伪 -Tubulin and phosphorylated Histone H2A.X was detected by Western blot. The inhibitory effects of NL-101 alone and in combination with bortezomib were investigated in the model of subcutaneous transplantation of RPMI 8226 multiple myeloma cells. The results showed that NL-101 could produce both HDAC inhibitors and DNA alkylators, which not only inhibited the deacetylation level of histone in tumor cells, but also increased DNA damage, and eventually induced cell cycle arrest and apoptosis. Both the cell level and the animal model of transplanted tumor showed strong antitumor activity, which was superior to the positive control drug mefallen, and the synergistic effect of the combination with bortezomib. NL-101 is expected to be a new anti-multiple myeloma drug.
【作者单位】：杭州民生药物研究院有限公司;中国药科大学基础医学与临床药学学院;
【分类号】：R96

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