Multiple myeloma regression mediated by bruceantin
Multiple myeloma regression mediated by bruceantin
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DOI：
10.1158/1078-0432.ccr-0362-3
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发表时间：
2004-02-01
影响因子：
11.5
通讯作者：
Pezzuto, JM
中科院分区：
文献类型：
--
作者：
Cuendet, M;Christov, K;Pezzuto, JM
目的：布鲁斯汀已被证明能诱导多种白血病和淋巴瘤细胞系的细胞分化。它还下调了c-MYC，表明下调与诱导细胞分化或细胞死亡相关。在本研究中，我们将重点放在多发性骨髓瘤上，使用RPMI 8226细胞系作为模型。实验设计：采用免疫印迹法、4′，6-二氨基-2-苯基吲哚染色法、caspase样活性评价法和3,3′-二己基碳蓝碘化染色法检测布鲁氏菌素对c-MYC水平和细胞凋亡的影响。采用RPMI 8226异种移植物在SCID小鼠中评估了灯芯素抑制原发肿瘤生长的潜力，并通过末端脱氧核苷酸转移酶介导的缺口末端标记法评估了肿瘤的凋亡情况。结果：在培养的RPMI 8226细胞中，布鲁斯汀作用24小时后，c-MYC被强烈下调。在U266和H929细胞中，布鲁斯汀没有以这种方式调节c-MYC。三种细胞系均诱导凋亡。在RPMI 8226细胞中，细胞凋亡是通过原aspase的蛋白水解加工和poly（adp -核糖）聚合酶的降解发生的。线粒体途径也参与其中。由于RPMI 8226细胞是最敏感的，因此它们被用于异种移植模型。布鲁斯汀治疗（2.5- 5mg /kg）导致肿瘤显著消退，无明显毒性。与对照肿瘤（14%）相比，用bruceantin处理的动物肿瘤（37%）的细胞凋亡显著增加。结论：在细胞培养和异种移植模型中，布鲁氏菌素干扰RPMI 8226细胞的生长。这些结果表明，应该重新研究灯盏素对多发性骨髓瘤和其他血液系统恶性肿瘤的临床疗效。
Purpose: Bruceantin has been shown to induce cell differentiation in a number of leukemia and lymphoma cell lines. It also down-regulated c-MYC, suggesting a correlation of down-regulation with induction of cell differentiation or cell death. In the present study, we focused on multiple myeloma, using the RPMI 8226 cell line as a model.Experimental Design: The effects of bruceantin on c-MYC levels and apoptosis were examined by immunoblotting, 4',6-diamidino-2-phenylindole staining, evaluation of caspase-like activity, and 3,3'-dihexyloxacarbocyanine iodide staining. The potential of bruceantin to inhibit primary tumor growth was assessed with RPMI 8226 xenografts in SCID mice, and apoptosis in the tumors was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay.Results: c-MYC was strongly down-regulated in cultured RPMI 8226 cells by treatment with bruceantin for 24 h. With U266 and H929 cells, bruceantin did not regulate c-MYC in this manner. Apoptosis was induced in the three cell lines. In RPMI 8226 cells, apoptosis occurred through proteolytic processing of procaspases and degradation of poly(ADP-ribose) polymerase. The mitochondrial pathway was also involved. Because RPMI 8226 cells were the most sensitive, they were used in a xenograft model. Bruceantin treatment (2.5-5 mg/kg) resulted in a significant regression of tumors without overt toxicity. Apoptosis was significantly elevated in tumors derived from animals treated with bruceantin (37%) as compared with the control tumors (14%).Conclusions: Bruceantin interferes with the growth of RPMI 8226 cells in cell culture and xenograft models. These results suggest that bruceantin should be reinvestigated for clinical efficacy against multiple myeloma and other hematological malignancies.