Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells
Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells
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DOI：
10.1182/blood.v91.11.4300.411k41_4300_4310
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发表时间：
1998-06-01
期刊：
影响因子：
20.3
通讯作者：
de Thé, H
中科院分区：
文献类型：
--
作者：
Giannì, M;Koken, MHM;de Thé, H
在急性早幼粒细胞白血病（APL）细胞系NB 4以及APL患者的细胞中，三氧化二砷（AS（2）O（3））导致细胞成熟不完全，诱导细胞凋亡，以及致癌PML/RAR α融合蛋白的降解。我们已经分离出一个砷抗性NB 4亚系（NB 4-As-R），它不能进行凋亡，但保持对这种药物的部分分化反应。当在AS（2）O（3）存在下生长时，NB 4-As-R细胞降解PML/RAR α，轻微分化，并且对血清缺乏诱导的凋亡变得更加敏感。同样，在RA耐药的NB 4-R1细胞中，RA诱导了显著的PML/RAR α降解，但未能诱导细胞成熟。因此，As 2 O3或维甲酸（RA）诱导的PML/RAR α降解可能是一个先决条件，但不足以对这些药物的完全分化/凋亡反应。值得注意的是，RA触发分化和凋亡大大加速As_2O_3处理NB_4-As-R细胞。这两种药物之间的协同作用，在这种情况下，可以提供一个联合或顺序RA/As 2 O3治疗的实验基础。(C)1998年，美国血液学会。
In the acute promyelocytic leukemia (APL) cell line NB4, as well as in APL patients' cells, arsenic trioxide (AS(2)O(3)) leads to incomplete cell maturation, induction of apoptosis, as well as to the degradation of the oncogenic PML/RAR alpha fusion protein. We have isolated an arsenic-resistant NB4 subline (NB4-As-R), which fails to undergo apoptosis, but maintains the partial differentiation response to this drug. When grown in the presence of AS(2)O(3), NB4-As-R cells degrade PML/RAR alpha, slightly differentiate, and become more sensitive to serum deprivation-induced apoptosis. Similarly, in RA-resistant NB4-R1 cells, RA induced a significant PML/RAR alpha degradation and yet failed to induce cell maturation. Thus, As2O3- or retinoic acid (RA)-induced PML/RAR alpha degradation may be a prerequisite, but is not sufficient for the full differentiative/apoptotic response to these drugs. Strikingly, RA triggered differentiation and apoptosis were greatly accelerated in As2O3-treated NB4-As-R cells. The synergism between these two agents in this setting could provide an experimental basis for combined or sequential RA/As2O3 therapies. (C) 1998 by The American Society of Hematology.