联合砷剂和维甲酸治疗可增强耐砷NB4细胞的分化和凋亡。

Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells.

作者信息

Giannì M, Koken M H, Chelbi-Alix M K, Benoit G, Lanotte M, Chen Z, de Thé H

机构信息

Centre National de la Recherche Scientifique Unité Propre de Recherche 9051, Laboratoire associé au Comité de Paris de la Ligue Contre le Cancer, UIH, Université Paris VII, Service de Biochimie B, Hôpital St Louis, Paris, France.

出版信息

Blood. 1998 Jun 1;91(11):4300-10.

PMID:9596679

Abstract

In the acute promyelocytic leukemia (APL) cell line NB4, as well as in APL patients' cells, arsenic trioxide (As2O3) leads to incomplete cell maturation, induction of apoptosis, as well as to the degradation of the oncogenic PML/RARalpha fusion protein. We have isolated an arsenic-resistant NB4 subline (NB4-AsR), which fails to undergo apoptosis, but maintains the partial differentiation response to this drug. When grown in the presence of As2O3, NB4-AsR cells degrade PML/RARalpha, slightly differentiate, and become more sensitive to serum deprivation-induced apoptosis. Similarly, in RA-resistant NB4-R1 cells, RA induced a significant PML/RARalpha degradation and yet failed to induce cell maturation. Thus, As2O3- or retinoic acid (RA)-induced PML/RARalpha 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-AsR cells. The synergism between these two agents in this setting could provide an experimental basis for combined or sequential RA/As2O3 therapies.

摘要

在急性早幼粒细胞白血病（APL）细胞系NB4以及APL患者的细胞中，三氧化二砷（As2O3）可导致细胞成熟不完全、诱导细胞凋亡以及致癌性早幼粒细胞白血病蛋白/维甲酸受体α（PML/RARα）融合蛋白降解。我们分离出了一个对砷耐药的NB4亚系（NB4-AsR），该亚系细胞不会发生凋亡，但对这种药物仍保持部分分化反应。当在As2O3存在的情况下生长时，NB4-AsR细胞会降解PML/RARα，轻微分化，并对血清剥夺诱导的凋亡变得更加敏感。同样，在对维甲酸（RA）耐药的NB4-R1细胞中，RA可诱导PML/RARα显著降解，但未能诱导细胞成熟。因此，As2O3或RA诱导的PML/RARα降解可能是一个先决条件，但对于对这些药物的完全分化/凋亡反应并不充分。引人注目的是，在经As2O3处理的NB4-AsR细胞中，RA触发的分化和凋亡大大加速。在这种情况下，这两种药物之间的协同作用可为联合或序贯使用RA/As2O3疗法提供实验依据。