The combination of UCN-01 and ATRA triggers differentiation in ATRA resistant acute promyelocytic leukemia cell lines via RAF-1 independent activation of MEK/ERK

被引：3
作者：
Liang, Cui [1 ,2 ]
Ding, Ming [3 ]
Weng, Xiang-qin [1 ,2 ]
Sheng, Yan [1 ,2 ]
Wu, Jing [1 ,2 ]
Cai, Xun [1 ,2 ]
机构：
[1] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, Shanghai Inst Hematol, 197 Rui Jin Rd 2, Shanghai 200025, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom, 197 Rui Jin Rd 2, Shanghai 200025, Peoples R China
[3] Cent Hosp Minhang Dist, Dept Hematol Oncol, 170 Xin Song Rd, Shanghai 201199, Peoples R China
来源：
FOOD AND CHEMICAL TOXICOLOGY | 2019年 / 126卷
基金：
上海市自然科学基金;
关键词：
Acute promyelocytic leukemia; All-trans retinoic acid; Differentiation; MEK; UCN-01; TRANS-RETINOIC ACID; PROTEIN-KINASE-C; PML-RAR-ALPHA; ARSENIC TRIOXIDE; GEMTUZUMAB OZOGAMICIN; C/EBP-BETA; INDUCE APOPTOSIS; MYELOMA CELLS; INHIBITORS; DELTA;
D O I：
10.1016/j.fct.2019.02.033
中图分类号：
TS2 [食品工业];
学科分类号：
0832 ;
摘要：
With the introduction of arsenic trioxide and all-trans retinoic acid, the prognosis of acute promyelocytic leukemia has greatly improved. However, all-trans retinoic acid resistance is still unresolved in acute promyelocytic leukemia relapsed patients. In this study, the clinical achievable concentration of 7-hydroxystaurosporine synergized with all-trans retinoic acid to induce terminal differentiation in all-trans retinoic acid resistant acute promyelocytic leukemia cell lines. Though 7-hydroxystaurosporine is a PKC inhibitor, PKC might not be involved in the combination-induced differentiation since other PKC selective inhibitors, Go 6976 and rottlerin failed to cooperate with all-trans retinoic acid to trigger differentiation. The combination significantly enhanced the protein level of CCAAT/enhancer binding protein beta and/or PU.1 as well as activated MEK/ERK. U0126 (MEK specific inhibitor) not only suppressed the combination-induced differentiation but also restored the protein level of CCAAT/enhancer binding protein beta and/or PU.1. However, RAF-1 inhibitor had no inhibitory effect on MEK activation and the combination-induced differentiation. Therefore, the combination overcame differentiation block via RAF-1 independent MEK/ERK modulation of the protein level of CCAAT/enhancer binding protein beta and/or PU.1. These findings may provide a preclinical rationale for the potential role of this combination in the treatment of all-trans retinoic acid resistant acute promyelocytic leukemia patients.
引用
收藏
页码：303 / 312
页数：10
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