Combination of enzastaurin and ATRA exerts dose-dependent dual effects on ATRA-resistant acute promyelocytic leukemia cells

American Journal of Cancer Research

Ming Ding¹  Cui Liang² 

[1] Department of Hematology Oncology, Central Hospital of Minhang District, No. 170 Xin Song Road, Shanghai 201199, China;Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui-Jin Road II, Shanghai 200025, China

关键词: Acute promyelocytic leukemia;    all-trans retinoic acid;    apoptosis;    differentiation;    enzastaurin;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

All-trans retinoic acid (ATRA) resistance continues to be a critical problem in acute promyelocytic leukemia (APL)-relapsed patients. In this study, a clinically achievable concentration of enzastaurin synergized with ATRA to induce differentiation and apoptosis in ATRA-resistant APL cell lines, NB4-R1 and NB4-R2. Mechanistically, although enzastaurin is a protein kinase Cβ (PKCβ) inhibitor, PKCβ may not be required since the activity of PKCβ was not suppressed by enzastaurin-ATRA (enz-ATRA) co-treatment, and another PKCβ-selective inhibitor did not mimic the effects of enzastaurin. An MEK inhibitor but not a RAF-1 inhibitor suppressed enz-ATRA treatment-triggered differentiation, activation of MEK/ERK and up-regulation of CCAAT/enhancer binding protein β (C/EBPβ) and/or PU.1. Therefore, RAF-1-independent MEK/ERK signaling was required for enz-ATRA treatment-induced differentiation via modulation of the protein levels of C/EBPβ and/or PU.1. Enz-ATRA treatment collapsed mitochondrial transmembrane potential without the activation of caspase-3, -6 and -7. Moreover, caspase-3/7- and caspase-6-specific inhibitors had no inhibitory effect on enz-ATRA treatment-triggered apoptosis. Therefore, enz-ATRA treatment-induced apoptosis was mitochondria-dependent but caspase-independent. Enz-ATRA treatment degraded PML-RARα, which may be involved in enz-ATRA treatment-induced dual effects and may also be beneficial for APL eradication. These findings may provide a potential therapy for ATRA-resistant APL patients.

【 授权许可】

CC BY-NC