Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming
Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming
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合成类维生素A和DNA去甲基化剂的组合通过视黄酸信号重编程诱导神经母细胞瘤的分化
DOI：
10.1038/s41416-021-01571-y
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发表时间：
2021
影响因子：
8.8
通讯作者：
Ushijima Toshikazu
中科院分区：
文献类型：
--
作者：
Hattori Naoko;Asada Kiyoshi;Miyajima Nozomu;Mori Akiko;Nakanishi Yoko;Kimura Kana;Wakabayashi Mika;Takeshima Hideyuki;Nitani Chika;Hara Junichi;Ushijima Toshikazu
研究背景神经母细胞瘤（NBL）的CpG岛甲基化表型与预后不良密切相关，5-氮杂-2 '-脱氧胞苷（5-aza-dC）可作为NBL的靶点。分化治疗是高风险NBL的标准维持治疗。然而，他米巴罗汀（一种合成的视黄酸）的体内作用及其与5-aza-dC组合的功效尚未研究。在这里，我们进行了临床前研究，以评估在体内他米巴罗汀的效果和combination.MethodsTreatment效果进行了分析，在体外细胞生长和分化状态，并在体内异种移植抑制。去甲基化基因进行了分析，DNA甲基化微阵列和genomic enrichment.ResultsTamibarotene单药治疗诱导神经延伸和上调的分化标志物的NBL细胞在体外，肿瘤消退没有严重的副作用在体内。5-Aza-dC单一疗法在体外和体内均抑制肿瘤生长，并诱导与神经系统发育和功能相关的基因的去甲基化。在体外用5-aza-dC预处理增强了参与视黄酸信号传导的分化标志物和基因的上调。预处理与5-aza-dC在体内显着抑制肿瘤的生长和减少的变化，肿瘤sizes.ConclusionsEpigenetic药物为基础的分化治疗，使用5-aza-dC和TBT是一个很有前途的策略难治性NBLs。
BackgroundThe CpG island methylator phenotype of neuroblastoma (NBL) is strongly associated with poor prognosis and can be targeted by 5-aza-2’-deoxycytidine (5-aza-dC). Differentiation therapy is a standard maintenance therapy for high-risk NBLs. However, the in vivo effect of tamibarotene, a synthetic retinoic acid, and the efficacy of its combination with 5-aza-dC have not been studied. Here, we conducted a preclinical study to assess the in vivo tamibarotene effect and the combination.MethodsTreatment effects were analysed by in vitro cell growth and differentiation state and by in vivo xenograft suppression. Demethylated genes were analysed by DNA methylation microarrays and geneset enrichment.ResultsTamibarotene monotherapy induced neural extension and upregulation of differentiation markers of NBL cells in vitro, and tumour regression without severe side effects in vivo. 5-Aza-dC monotherapy suppressed tumour growth both in vitro and in vivo, and induced demethylation of genes related to nervous system development and function. Pre-treatment with 5-aza-dC in vitro enhanced upregulation of differentiation markers and genes involved in retinoic acid signaling. Pre-treatment with 5-aza-dC in vivo significantly suppressed tumour growth and reduced the variation in tumour sizes.ConclusionsEpigenetic drug-based differentiation therapy using 5-aza-dC and TBT is a promising strategy for refractory NBLs.
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影响因子：
5.7
作者：
Diesch J;Zwick A;Garz AK;Palau A;Buschbeck M;Götze KS
通讯作者：
Götze KS
Am80 诱导人神经母细胞瘤 NH-12 细胞系的神经元分化。
影响因子：
5.4
作者：
Hideo Shiohira;A. Kitaoka;H. Shirasawa;M. Enjoji;M. Nakashima
通讯作者：
M. Nakashima
DOI：
--
发表时间：
1999
期刊：
The New England journal of medicine
影响因子：
--
作者：
K. Matthay;J. Villablanca;R. C. Seeger;D. Stram;R. E. Harris;N. Ramsay;P. Swift;H. Shimada;C. T. Black;G. M. Brodeur;R. Gerbing;C. P. Reynolds
通讯作者：
K. Matthay;J. Villablanca;R. C. Seeger;D. Stram;R. E. Harris;N. Ramsay;P. Swift;H. Shimada;C. T. Black;G. M. Brodeur;R. Gerbing;C. P. Reynolds
一种新的人神经母细胞瘤细胞系：生物学特性、细胞遗传学和 N-myc 癌基因分析。
DOI：
--
发表时间：
1990
期刊：
影响因子：
--
作者：
Toshimitsu Suzuki;M. Hirota;M. Iwabuchi;N. Nomura;F. Saito
通讯作者：
F. Saito
影响因子：
11.2
作者：
Wang C;Liu Z;Woo CW;Li Z;Wang L;Wei JS;Marquez VE;Bates SE;Jin Q;Khan J;Ge K;Thiele CJ
通讯作者：
Thiele CJ