Altered conjugate formation and altered apoptosis of multidrug-resistant human leukemia cell line affects susceptibility to killing by activated natural killer (NK) cells.
Altered conjugate formation and altered apoptosis of multidrug-resistant human leukemia cell line affects susceptibility to killing by activated natural killer (NK) cells.
复制标题
多重耐药人白血病细胞系结合物形成的改变和细胞凋亡的改变会影响对激活的自然杀伤 (NK) 细胞杀伤的敏感性。
DOI：
10.1002/ijc.11555
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发表时间：
2004
影响因子：
6.4
通讯作者：
Wee,Kathleen
中科院分区：
文献类型：
--
作者：
Treichel,RobinS;Bunuan,Michael;Hahn,Nancy;Wee,Kathleen
大多数表现出P-糖蛋白（P-gp）相关多药耐药（MDR）的白血病表现出对自然杀伤（NK）细胞介导的免疫细胞毒性的敏感性降低。为了探索这一现象，我们研究了N6/ADR，一种多柔比星选择的，P-gp阳性的人急性淋巴细胞白血病（ALL）细胞系NALM 6的变体。评价NK细胞溶解途径的每个阶段（结合、活化和杀伤），以确定导致变体细胞毒性相对于其药物敏感亲本系降低的变化。对NK细胞溶解的敏感性降低的主要原因被发现是MDR变体减少的缀合物形成。亲本细胞和MDR细胞激活NK效应子，同时释放肿瘤坏死因子-α（TNF-α），与结合物形成相关。N6/ADR也比NALM 6对抗体依赖性细胞毒性和从NK细胞释放的细胞毒性因子更具抗性，如通过51 Cr释放和DNA片段化测量的。这是第一份关于P-gp阳性白血病细胞系的报告，该细胞系表现出结合物形成减少以及对NK介导的杀伤机制的抗性增加。我们的结果表明，使用基于NK的免疫疗法作为多药耐药白血病的替代治疗时应谨慎。© 2003 Wiley利斯公司
Most leukemias that exhibit P‐glycoprotein (P‐gp)‐associated multidrug resistance (MDR) exhibit reduced susceptibility to immune cytotoxicity mediated by natural killer (NK) cells. To explore this phenomenon we investigated N6/ADR, a doxorubicin‐selected, P‐gp‐positive variant of the human acute lymphoblastic leukemia (ALL) cell line NALM6. Each stage of the NK cytolytic pathway, (binding, activation and killing) was evaluated to identify the alterations responsible for the reduced cytotoxicity of the variant relative to its drug‐sensitive parental line. The major cause of the decreased susceptibility to NK cytolysis was found to be reduced conjugate formation by the MDR variant. Activation of NK effectors by parental and MDR cells with concomitant release of tumor necrosis factor‐alpha (TNF‐α) correlated with conjugate formation. N6/ADR was also more resistant than NALM6 to antibody‐dependent cellular cytotoxicity and to cytotoxic factors released from NK cells as measured both by51Cr‐release and by DNA fragmentation. This is the first report of a P‐gp‐positive leukemic line that exhibits reduced conjugate formation as well as increased resistance to NK‐mediated killing mechanisms. Our results suggest caution in the use of NK‐based immunotherapy as an alternative treatment for multidrug‐resistant leukemias. © 2003 Wiley‐Liss, Inc.