N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes
N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes
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DOI：
10.1038/sj.leu.2402485
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发表时间：
2002-05-01
期刊：
影响因子：
11.4
通讯作者：
Maurer, BJ
中科院分区：
文献类型：
--
作者：
O'Donnell, PH;Guo, WX;Maurer, BJ
类维生素A，N-（4-羟基苯基）维A酰胺（4-HPR），介导p53非依赖性细胞毒性，并能增加活性氧和神经酰胺在实体瘤细胞系。我们在6种人急性淋巴细胞白血病（ALL）细胞系中测定了用4-HPR（3-12 μ M）处理后神经酰胺和细胞毒性的变化：T细胞（MOLT-3，MOLT-4，CEM），前B细胞（NALM-6，SMS-SB）和空细胞（NALL-1）。暴露于4-HPR（12 μ M）96小时导致4.7（MOLT-3）、3.5（MOLT-4）、3.9（CEM）、2.9（NALM-6）、4.7（SMS-SB）和4.5（NALL-1）log的细胞杀伤。所有六个细胞系杀死99%细胞的平均4-HPR浓度（LCgg）为4.8 μ M（范围：1.5-8.9 μ M）。用4-HPR（9 μ M）处理24小时导致神经酰胺增加8.9 ± 1.0倍（范围：4.9-15.7倍）。神经酰胺增加具有时间和剂量依赖性，并可被神经酰胺从头合成抑制剂消除。在6个ALL细胞系中的4个中，通过d，1-苏型-（1-苯基-2-十六酰基-氨基-3-吗啉代-1-丙醇）（PPMP）同时抑制神经酰胺糖基化/酰化进一步增加神经酰胺水平，并协同增加4-HPR细胞毒性。4-HPR对外周血单个核细胞和淋巴母细胞系的细胞毒性最小，
The retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), mediates p53-independent cytotoxicity and can increase reactive oxygen species and ceramide In solid tumor cell lines. We determined changes In ceramide and cytotoxicity upon treatment with 4-HPR (3-12 muM) In six human acute lymphoblastic leukemia (ALL) cell lines: T cell (MOLT-3, MOLT-4, CEM), pre-B-cell (NALM-6, SMS-SB), and null cell (NALL-1). Exposure to 4-HPR (12 muM) for 96 h caused 4.7 (MOLT-3), 3.5 (MOLT-4), 3.9 (CEM), 2.9 (NALM-6), 4.7 (SMS-SB), AND 4.5 (NALL-1) logs of cell kill. The average 4-HPR concentration that killed 99% of cells (LCgg) for all six lines was 4.8 muM (range: 1.5-8.9 muM). Treatment with 4-HPR (9 muM) for 24 h resulted in an 8.9 +/- 1.0-fold (range: 4.9-15.7-fold) increase of ceramide. Ceramide increase was time- and dose-dependent and abrogated by inhibitors of do novo ceramide synthesis. Concurrent inhibition of ceramide glycosylation/acylation by d,1-threo-(1-phenyl-2-hexadecanoyl-amino-3-morpholino-1-propanol) (PPMP) further increased ceramide levels, and synergistically increased 4-HPR cytotoxicity in four of six ALL cell lines. 4-HPR was minimally cytotoxic to peripheral blood mononuclear cells and a lymphoblastoid cell line, and increased ceramide