Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia
Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia
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DOI：
10.1182/blood-2010-02-271080
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发表时间：
2010-11-18
期刊：
影响因子：
20.3
通讯作者：
Loughran, Thomas P., Jr.
中科院分区：
文献类型：
--
作者：
Liu, Xin;Ryland, Lindsay;Loughran, Thomas P., Jr.
自然杀伤（NK）型侵袭性大颗粒淋巴细胞（LGL）白血病是一种追求快速临床病程的致命疾病。目前尚无有效的治疗方法，其发病机制尚不明确。在这里，我们报告的生存素是高表达的侵袭性和慢性白血病NK细胞，而不是在正常的NK细胞。在体外治疗人类和大鼠NK-LGL白血病细胞与细胞可渗透的，短链C-6-神经酰胺（C-6）的纳米脂质体制剂导致半胱天冬酶依赖性细胞凋亡和减少生存素蛋白表达，在时间和剂量依赖性的方式。重要的是，全身静脉内递送纳米脂质体神经酰胺在侵袭性NK-LGL白血病的同系Fischer F344大鼠模型中诱导完全缓解。治疗效果与生存素在体内的表达降低有关。这些数据表明，通过递送纳米脂质体C-6-神经酰胺体内靶向生存素可能是致命性白血病的有希望的治疗方法。（血。2010;116（20）：4192-4201）
The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C-6-ceramide (C-6) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time-and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C-6-ceramide may be a promising therapeutic approach for a fatal leukemia. (Blood. 2010;116(20):4192-4201)