一种小分子在 mRNA 水平上显著抑制人慢性髓系白血病的 bcr/abl 融合基因。

A small molecule significantly inhibits the bcr/abl fusion gene at the mRNA level in human chronic myelogenous leukemia.

机构信息

Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

出版信息

Leuk Res. 2011 Aug;35(8):1074-9. doi: 10.1016/j.leukres.2010.11.012. Epub 2010 Dec 15.

DOI:10.1016/j.leukres.2010.11.012

Abstract

Bcr/abl fusion gene is the marker gene in chronic myelogenous leukemia (CML) and becomes the target for CML therapy. Although Imatinib opened a new way to treat CML, the resistance to the drug caused by bcr/abl fusion protein mutation stimulated search for new molecules to inhibit bcr/abl expression. In our research, it was found that a novel 2-aminosteroid (H89465) possessed special mechanism in treating CML. H89465 inhibits the proliferation of both non-resistant and resistant CML cells such as K562, Meg-01 and clinical primary CML cells. It prolongs the survival time of NOD/SCID mice inoculated with K562 leukemia cells. The mechanism underlying the effects is concerned with down-regulation of bcr/abl mRNA expression followed by decreasing the BCR/ABL protein expression and tyrosine kinase activity in CML cells. Our results demonstrate that H89465 possesses the therapeutic potential in treating human CML.

摘要

bcr/abl 融合基因是慢性髓系白血病（CML）的标记基因，成为 CML 治疗的靶点。虽然伊马替尼为 CML 治疗开辟了新途径，但 bcr/abl 融合蛋白突变导致的耐药性刺激了寻找新的分子来抑制 bcr/abl 表达的研究。在我们的研究中，发现一种新型 2-氨基甾体（H89465）在治疗 CML 方面具有特殊机制。H89465 抑制非耐药和耐药 CML 细胞（如 K562、Meg-01 和临床原发性 CML 细胞）的增殖。它延长了接种 K562 白血病细胞的 NOD/SCID 小鼠的存活时间。其作用机制与下调 bcr/abl mRNA 表达有关，随后降低 CML 细胞中的 BCR/ABL 蛋白表达和酪氨酸激酶活性。我们的结果表明，H89465 具有治疗人类 CML 的潜力。