Cellular distribution studies of the nitric oxide-generating antineoplastic prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate formulated in Pluronic P123 micelles.
Cellular distribution studies of the nitric oxide-generating antineoplastic prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate formulated in Pluronic P123 micelles.
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DOI：
10.1111/jphp.12100
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Shami PJ
中科院分区：
文献类型：
--
作者：
Kaur I;Terrazas M;Kosak KM;Kern SE;Boucher KM;Shami PJ
一氧化氮（NO）具有抗肿瘤活性。它能诱导急性髓性白血病（AML）细胞分化和凋亡。一氧化氮前药O2-（2,4-二硝基苯基）1-[（4-乙氧羰基）哌嗪-1-基]重氮-1-ium-1,2-二酸酯或JS-K具有有效的抗白血病活性。JS-K在体外和体内对多发性骨髓瘤、前列腺癌、非小细胞肺癌、胶质瘤和肝癌也有活性。使用Pluronic®P123聚合物，我们为JS-K开发了一种胶束配方，以提高其溶解度和稳定性。本研究的目的是研究JS-K在AML细胞中的细胞分布。我们用HL-60 AML细胞研究了游离药物JS-K和P123胶束中配制的JS-K （P123/JS-K）在细胞内的分布。我们还研究了JS-K对细胞质和核细胞部分蛋白质的s -谷胱甘肽化作用。游离的JS-K和P123/JS-K主要在细胞核中积累。游离JS-K和P123/JS-K均诱导核蛋白s -谷胱甘肽化，但P123/JS-K的作用更为明显。观察到细胞质蛋白的s -谷胱甘肽化极少。我们得出的结论是，胶束配方的JS-K增加了其在细胞核中的积累。通过s -谷胱甘肽化的翻译后蛋白修饰可能有助于JS-K的抗白血病特性。
Nitric oxide (NO) possesses anti-tumor activity. It induces differentiation and apoptosis in acute myeloid leukemia (AML) cells. The NO prodrug O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate, or JS-K, has potent antileukemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small cell lung cancer, glioma and liver cancer. Using the Pluronic® P123 polymer, we have developed a micelle formulation for JS-K in order to increase its solubility and stability. The goal of the current study was to investigate the cellular distribution of JS-K in AML cells. We investigated the intracellular distribution of JS-K (free drug) and JS-K formulated in P123 micelles (P123/JS-K) using HL-60 AML cells. We also studied the S-glutathionylating effects of JS-K on proteins in the cytoplasmic and nuclear cellular fractions. Both free JS-K and P123/JS-K accumulate primarily in the nucleus. Both free JS-K and P123/JS-K induced S-glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS-K. Minimal S-glutathionylation of cytoplasmic proteins was observed. We conclude that a micelle formulation of JS-K increases its accumulation in the nucleus. Post-translational protein modification through S-glutathionylation may contribute to JS-K’s anti-leukemic properties.
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影响因子：
3.8
作者：
Rapoport, N;Marin, A;Muniruzzaman, M
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作者：
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5.2
作者：
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通讯作者：
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