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

• Published in: Food and chemical toxicology 2019-04, Vol.126, p.303-312
• Main Authors: Liang, Cui, Ding, Ming, Weng, Xiang-qin, Sheng, Yan, Wu, Jing, Cai, Xun
• Format: Article
• Language: English
• Subjects: Acute promyelocytic leukemia; All-trans retinoic acid; Differentiation; MEK; UCN-01
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2019.02.033

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, Gö 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 β 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 β 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 β 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.