Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells.
Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells.
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DOI：
10.1038/sj.bjc.6602398
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发表时间：
2005-02-28
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
最近的数据表明，全反式维甲酸(ATRA)的异构化是13-顺式维甲酸(13-cisRA)治疗神经母细胞瘤具有良好临床特性的关键机制。维甲酸(RA)代谢被认为与耐药性有关，调节这种代谢的策略可能会增加13cisRA的临床疗效。本研究的目的是验证这样一种假设，即优先与细胞维甲酸结合蛋白(CRABPs)结合的维甲酸类化合物(如阿维A素)或RA羟基酶特异性抑制剂(如R116010)可以增加ATRA的细胞内利用度。用阿维A(50 μM)或R116010(1或10 μM)与10 μM全反式维甲酸或13顺式维甲酸共同孵育SH-SY5Y细胞，可选择性增加细胞内全反式维甲酸水平，而对13顺式维甲酸水平无影响。RA可诱导SH-SY5Y细胞产生CRABP。相反，在RA治疗后CRABP诱导很少或没有诱导的神经母细胞瘤细胞系中，阿维A对细胞内维甲酸浓度没有显著影响。ATRA和13cisRA均能显著诱导SH-SY5Y细胞中CYP26A1的表达，而R116010可增强RA诱导的报告基因和细胞色素P26A1的表达。神经母细胞瘤细胞对R116010的反应与对CYP26的抑制一致，提示抑制RA代谢可能进一步优化神经母细胞瘤的维甲酸治疗。
Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.
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影响因子：
3.6
作者：
Marill, J;Cresteil, T;Chabot, GG
通讯作者：
Chabot, GG
影响因子：
4.8
作者：
Dong, D;Ruuska, SE;Noy, N
通讯作者：
Noy, N
DOI：
10.1002/1096-911x(20010101)36:1
发表时间：
2001-01-01
期刊：
MEDICAL AND PEDIATRIC ONCOLOGY
影响因子：
--
作者：
Ponthan, F;Borgström, P;Kogner, P
通讯作者：
Kogner, P
影响因子：
2.6
作者：
Blaese, MA;Santo-Hoeltje, L;Rodemann, HP
通讯作者：
Rodemann, HP
影响因子：
158.5
作者：
Matthay, KK;Villablanca, JG;Reynolds, CP
通讯作者：
Reynolds, CP