Kuo Hsing-Chun, Kuo Wu-Hsien, Lee Yean-Jang, Wang Chau-Jong, Tseng Tsui-Hwa
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan.
Toxicol Appl Pharmacol. 2006 Oct 1;216(1):80-8. doi: 10.1016/j.taap.2006.04.007.
All-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL); however, the response is sometimes very slow. Furthermore, relapse and resistance to treatment often occur despite continued treatment with ATRA. Thereafter, combination treatment strategies have been suggested to circumvent these problems. The present study demonstrates that caffeic acid phenethyl ester (CAPE), a major component of honeybee propolis, enhanced ATRA-induced granulocytic differentiation in HL-60, a human promyelocytic cell line. The differentiation was assessed by Wright-Giemsa stain, nitroblue tetrazolium reduction, and membrane differentiation marker CD11b. In addition, CAPE enhanced ATRA-induced cell cycle arrest at the G1 phase by decreasing the association of cdk2-cyclin E complex. Finally, it was demonstrated that CAPE promoted the ATRA-mediated nuclear transcription activation of RARalpha assessed by EMSA assay and enhanced the expression of target genes including RARalpha, C/EBPepsilon, and p21 protein resulting in the differentiation development of leukemia. It is suggested that CAPE possesses the potential to enhance the efficiency of ATRA in the differentiation therapy of APL.
全反式维甲酸（ATRA）可使高比例的急性早幼粒细胞白血病（APL）患者实现完全缓解；然而，缓解过程有时非常缓慢。此外，尽管持续使用ATRA治疗，仍常出现复发和治疗抵抗的情况。此后，有人提出联合治疗策略来解决这些问题。本研究表明，蜜蜂蜂胶的主要成分咖啡酸苯乙酯（CAPE）可增强ATRA诱导的人早幼粒细胞系HL-60的粒细胞分化。通过瑞氏-吉姆萨染色、硝基蓝四氮唑还原试验和膜分化标志物CD11b来评估分化情况。此外，CAPE通过减少cdk2-细胞周期蛋白E复合物的结合，增强了ATRA诱导的细胞周期在G1期的停滞。最后，通过电泳迁移率变动分析（EMSA）试验证明，CAPE促进了ATRA介导的RARα核转录激活，并增强了包括RARα、C/EBPε和 p21蛋白在内的靶基因的表达，从而导致白血病的分化发展。提示CAPE具有提高ATRA在APL分化治疗中疗效的潜力。
