Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells
Beta-irradiation used for systemic radioimmunotherapy induces apoptosis and activates apoptosis pathways in leukaemia cells
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DOI：
10.1007/s00259-003-1216-z
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发表时间：
2003-09-01
影响因子：
9.1
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Friesen, C;Lubatschofski, A;Debatin, KM
用于全身放射免疫治疗 (RIT) 的 β 照射是治疗高危白血病和淋巴瘤的一种有前途的治疗方法。在骨髓选择性放射免疫治疗中，使用碘 131、钇 90 或铼 188 标记的放射免疫结合物进行 β 照射。然而，β-辐射诱导细胞死亡的机制在分子水平上尚不清楚。在这里，我们报告说，β-辐射根据剂量、时间点和剂量率诱导白血病细胞凋亡并激活凋亡途径。 β-辐射后，检测到 CD95 配体和 CD95 受体的上调，并发现半胱天冬酶的激活导致细胞凋亡。这些效应被广谱 caspase 抑制剂 zVAD-fmk 完全阻断。此外，辐射介导的线粒体损伤导致线粒体膜电位、caspase-9 激活和细胞色素 c 释放的扰动。 Bax（一种死亡促进蛋白）上调，Bcl-x（L）（一种死亡抑制蛋白）下调。我们还发现，与相同剂量率下的 β 照射相比，γ 照射后细胞凋亡率更高，细胞凋亡途径更早激活。此外，抗辐射细胞对CD95具有交叉抗性，而CD95抗性细胞对辐射具有交叉抗性，表明CD95和辐射至少部分地使用相同的效应途径。这些发现表明，β-辐射可利用线粒体和死亡受体途径诱导白血病细胞凋亡并激活凋亡途径。了解β-辐射介导的细胞凋亡的时间、顺序和分子途径可能有助于合理调整化疗和放疗策略。
Beta-irradiation used for systemic radioimmunotherapy (RIT) is a promising treatment approach for high-risk leukaemia and lymphoma. In bone marrow-selective radioimmunotherapy, beta-irradiation is applied using iodine-131, yttrium-90 or rhenium-188 labelled radioimmunoconjugates. However, the mechanisms by which beta-irradiation induces cell death are not understood at the molecular level. Here, we report that beta-irradiation induced apoptosis and activated apoptosis pathways in leukaemia cells depending on doses, time points and dose rates. After beta-irradiation, upregulation of CD95 ligand and CD95 receptor was detected and activation of caspases resulting in apoptosis was found. These effects were completely blocked by the broad-range caspase inhibitor zVAD-fmk. In addition, irradiation-mediated mitochondrial damage resulted in perturbation of mitochondrial membrane potential, caspase-9 activation and cytochrome c release. Bax, a death-promoting protein, was upregulated and Bcl-x(L), a death-inhibiting protein, was downregulated. We also found higher apoptosis rates and earlier activation of apoptosis pathways after gamma-irradiation in comparison to beta-irradiation at the same dose rate. Furthermore, irradiation-resistant cells were cross-resistant to CD95 and CD95-resistant cells were cross-resistant to irradiation, indicating that CD95 and irradiation used, at least in part, identical effector pathways. These findings demonstrate that beta-irradiation induces apoptosis and activates apoptosis pathways in leukaemia cells using both mitochondrial and death receptor pathways. Understanding the timing, sequence and molecular pathways of beta-irradiation-mediated apoptosis may allow rational adjustment of chemo- and radiotherapeutic strategies.