强心甾类固醇诱导Raji细胞凋亡的机理研究

Eexploration of cardiac glycosides (CTS) for the treatment of tumors has become the hot spot with the research of CTS in-depth and the report of effective clinical experiments for CTS treatment of solid tumors. Until now, the research of CTS on blood malignancies has not been systematized. In our previous work, we found that low dose of CTS without inhibition of Na,K-ATPase (NKA) activity could selectively induce blood malignancy cells apoptosis, Burkitt's lymphoma cells (Raji) was the most sensitive cells. CTS could inhibit Raji cells' overexpression c-myc and NF-κB activity. But the selective mechanism of CTS on blood malignancy cells is still unclear. Our findings suggest that the selective effect of CTS on Raji cells may be related to the regulation effect of CTS / NKA signaling pathway on these abnormal overexpression proteins.On the basis of our pre-discovery, this study will further elaborated on the following questions:1) To establish a causal relationship between CTS signaling pathway and Raji cells' sensitivity.To explore the consequences of blocking CTS signaling pathway. This can prove that CTS through NKA/IP3R/Src signaling pathway regulate the activity of NF-κB and c-myc and induce Raji cells apoptosis; 2) To investigate the CTS efficacy through in vivo study;3) To explore the effects of CTS on normal bone marrow cells. We hope through our study we can find a new target medicine for Burkitt's lymphoma.

随着强心甾类固醇（CTS）治疗肿瘤研究的深入及对实体瘤临床实验有效的报道，探索CTS治疗肿瘤成为当前热点。目前CTS对血液肿瘤研究缺乏系统性。我们最新研究发现：小剂量CTS在不抑制钠，钾-ATP酶（NKA）活性时选择性诱导血液肿瘤细胞凋亡，伯基特淋巴瘤细胞（Raji）最为敏感。CTS抑制Raji过度表达的c-myc及NF-κB活性。但CTS细胞选择性作用机理仍不清楚。我们的发现提示CTS对Raji选择作用可能与其异常表达蛋白受CTS/NKA信号调控有关。本研究拟在前期发现基础上，对以下问题作进一步阐述：1）建立CTS信号通路与Raji敏感的因果关系，探讨阻断CTS通路的后果，即证明CTS通过NKA/IP3R/Src通路调控NF-κB及c-myc从而诱导Raji细胞凋亡；2）体内实验探讨CTS疗效；3）探索CTS对正常骨髓细胞影响。我们的研究可能为找到治疗伯基特淋巴瘤的靶向药物提供科学基础。

随着强心甾类固醇（CTS）治疗肿瘤研究的深入及对实体瘤临床实验有效的报道，探索CTS治疗肿瘤成为当前热点。目前CTS对血液肿瘤研究缺乏系统性。我们最新研究发现：小剂量CTS在不抑制钠，钾-ATP酶（NKA）活性时选择性诱导血液肿瘤细胞凋亡，伯基特淋巴瘤细胞（Raji）最为敏感。CTS抑制Raji过度表达的c-myc及NF-κB活性。但CTS细胞选择性作用机理仍不清楚。我们的发现提示CTS对Raji选择作用可能与其异常表达蛋白受CTS/NKA信号调控有关。本研究在前期发现基础上，进一步研究发现：1）CTS通过NKA/IP3R/Src通路调控NF-κB及c-myc从而诱导Raji细胞凋亡；2）构建Raji淋巴瘤小鼠模型，证明CTS可有效治疗Raji淋巴瘤；3）CTS对正常骨髓细胞增殖及凋亡无影响。我们的研究为CTS用于临床治疗淋巴瘤提供了科学基础。