| Ibrutinib抑制弥漫大B细胞淋巴瘤细胞生存的作用研究 |
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| 引用本文： | 吴东维,夏冰,吴凌,许雯,宁乔杨,袁田,王超雨,晋鑫,于泳,张翼鷟. Ibrutinib抑制弥漫大B细胞淋巴瘤细胞生存的作用研究[J]. 中国肿瘤临床, 2017, 44(18): 903-908. DOI: 10.3969/j.issn.1000-8179.2017.18.676 |
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| 作者姓名： | 吴东维 夏冰 吴凌 许雯 宁乔杨 袁田 王超雨 晋鑫 于泳 张翼鷟 |
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| 作者单位： | 天津医科大学肿瘤医院血液科, 国家肿瘤临床医学研究中心, 天津市肿瘤防治重点实验室, 天津市恶性肿瘤临床医学研究中心 (天津市 300060) |
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| 基金项目： | the National Natural Science Foundation of China(No.81600163 and 81570201)本文课题受国家自然科学基金项目(81600163、81570201) |
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| 摘 要： | 目的 探讨Bruton酪氨酸激酶（Bruton's tyrosine kinase，BTK）抑制剂ibrutinib抑制弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma，DLBCL）细胞生存的作用及其相关机制。 方法 用不同浓度的ibrutinib处理DLBCL细胞系SUDHL-10、HBL-1和患者原代细胞，以MTT法检测细胞的增殖抑制情况；以Annexin V/PI流式细胞术和DAPI染色法检测细胞的凋亡情况；应用Western blot法检测细胞表达磷酸化BTK、AKT、ERK的变化。DLBCL细胞与MSC共培养后，体外克隆形成实验和NOD/SCID肿瘤模型小鼠检测ibrutinib在肿瘤微环境里对DLBCL细胞的抑制作用。 结果 2.5μmol/L及更高浓度的ibrutinib对DLBCL细胞的增殖有明显的抑制作用，且呈剂量依赖性。1.0、2.5μmol/L ibrutinib作用于SUDHL-10细胞24 h，细胞凋亡率分别为（21.73±3.64）%和（34.71±2.36）%，高于对照组（3.55±1.89）%（P < 0.05）。5、10μmol/L ibrutinib处理24 h后，DLBCL细胞系均出现核皱缩（5μmol/L）、碎裂（10μmol/L）。ibrutinib处理细胞后磷酸化BTK、AKT、ERK的表达均明显降低。ibrutinib抑制共培养时DLBCL细胞的体外克隆形成（P < 0.01）及DLBCL细胞在体内的增殖生长，差异均具有统计学意义（P < 0.05）。 结论 ibrutinib可抑制细胞系SUDHL-10和HBL-1的增殖，诱导凋亡，其机制可能通过阻断AKT、ERK信号途径而实现；在肿瘤微环境中ibrutinib同样对DLBCL细胞具有较强的抑制生存的作用，该药物有望为DLBCL的治疗带来希望。
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| 关 键 词： | 弥漫大B细胞淋巴瘤 ibrutinib 增殖 凋亡 |
| 收稿时间： | 2017-06-16 |
Ibrutinib inhibits diffuse large B-cell lymphoma cell survival |
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| Dongwei WU,Bing XIA,Ling WU,Wen XU,Qiaoyang NING,Tian YUAN,Chaoyu WANG,Xin JIN,Yong YU,Yizhuo ZHANG. Ibrutinib inhibits diffuse large B-cell lymphoma cell survival[J]. Chinese Journal of Clinical Oncology, 2017, 44(18): 903-908. DOI: 10.3969/j.issn.1000-8179.2017.18.676 |
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| Authors: | Dongwei WU Bing XIA Ling WU Wen XU Qiaoyang NING Tian YUAN Chaoyu WANG Xin JIN Yong YU Yizhuo ZHANG |
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| Affiliation: | Department of Hematology Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China |
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| Abstract: | Objective:To illustrate the effect and mechanism of ibrutinib,a Bruton's tyrosine kinase(BTK)inhibitor that inhibits diffuse large B-cell lymphoma(DLBCL)cell survival.Methods:DLBCL cell lines SUDHL-10 and HBL-1 were treated with ibrutinib at different concentrations.A MTT assay was used to detect the inhibition of cell proliferation.Cell apoptosis was analyzed by Annexin V-binding assay,as well as flow cytometry and DAPI staining.The expression of phosphorylated BTK,AKT and ERK was detected by Western blot. DLBCL cells were co-cultured with MSC.The inhibitory effect of ibrutinib on DLBCL cells in tumor microenvironment was assessed in clonogenicity in vitro and in a tumor-bearing non-obese diabetic/severe combined immunodeficient mice in vivo.Results:Up to 2.5 μmol/L and high concentrations of ibrutinib significantly inhibited the proliferation of DLBCL cells in a dose-dependent manner.Approx-imately 1 and 2.5 μmol/L ibrutinib was added on SUDHL-10 cells for 24 h,and the cell apoptotic rates were(21.73±3.64)% and(34.71± 2.36)%,respectively.Both were superior to that of the control group(3.55±1.89)%(P<0.05).Both two DLBCL cell lines pretreated with 5 and 10 μmol/L ibrutinib for 24 h and exhibited nuclear shrinkage at 5 μmol/L and nuclear fragmentation at 10 μmol/L.The expres-sion of phosphorylated BTK,AKT,and ERK decreased significantly after ibrutinib treatment.Ibrutinib inhibited clonogenicity in vitro(P<0.01)and cell proliferation and growth in vivo of DLBCL cells in co-culture system.The differences were statistically significant.Conclu-sion:Ibrutinib can inhibit the proliferation and induce apoptosis of SUDHL-10 and HBL-1 cell lines through a mechanism of blocking the AKT and ERK signaling pathways,as well as the proliferation of DLBCL cells in tumor microenvironment.This finding can significant-ly benefit DLBCL treatment. |
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| Keywords: | diffuse large B-cell lymphoma ibrutinib proliferation apoptosis |
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