Habib A, Hamade E, Mahfouz R, Nasrallah M S, de Thé H, Bazarbachi A
Department of Biochemistry, American University of Beirut, Beirut, Lebanon.
Leukemia. 2008 Jun;22(6):1125-30. doi: 10.1038/leu.2008.59. Epub 2008 Mar 20.
In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) triggers cell differentiation, while arsenic trioxide (As(2)O(3)) generates partial differentiation and apoptosis. Animal and human studies suggest that newly diagnosed APL patients can be cured using As(2)O(3) combined with ATRA. Cyclooxygenases are involved in prostaglandins and thromboxane synthesis. We have recently demonstrated that ATRA induces cyclooxygenase-1 (COX-1) expression and prostaglandin synthesis in NB4 cells and in blasts from patients with APL. In the present study we investigated the effect of ATRA and As(2)O(3) co-treatment on COX-1 expression and prostaglandin formation and tested the effect of the COX-1/COX-2 nonselective inhibitor indomethacin on cell differentiation. Arsenic treatment of NB4 cells resulted in a partial but significant reduction of ATRA-dependent induction of COX-1 expression and activity. Pretreatment of NB4 cells with indomethacin significantly impaired ATRA/As(2)O(3)-induced differentiation, as assessed by cell morphology, nitroblue tetrazolium test or CD11c expression. PGE(2) reversed the negative effect of indomethacin on differentiation of ATRA/As(2)O(3)-treated NB4 cells. In conclusion, COX-1 contributes to ATRA-dependent maturation of NB4 cells and is affected by As(2)O(3). These results also suggest that nonsteroidal antiinflammatory drugs should be avoided in APL patients treated with the combination of ATRA and As(2)O(3).
在急性早幼粒细胞白血病（APL）中，全反式维甲酸（ATRA）可触发细胞分化，而三氧化二砷（As₂O₃）则可诱导部分分化并引发凋亡。动物和人体研究表明，新诊断的APL患者可通过As₂O₃与ATRA联合使用得以治愈。环氧化酶参与前列腺素和血栓素的合成。我们最近证实，ATRA可诱导NB4细胞以及APL患者原始细胞中环氧化酶-1（COX-1）的表达和前列腺素的合成。在本研究中，我们调查了ATRA与As₂O₃联合治疗对COX-1表达和前列腺素形成的影响，并测试了COX-1/COX-2非选择性抑制剂吲哚美辛对细胞分化的作用。用砷处理NB4细胞导致ATRA依赖性COX-1表达和活性的诱导出现部分但显著的降低。用吲哚美辛预处理NB4细胞显著损害了ATRA/As₂O₃诱导的分化，这通过细胞形态学、硝基蓝四氮唑试验或CD11c表达进行评估。前列腺素E₂（PGE₂）逆转了吲哚美辛对经ATRA/As₂O₃处理的NB4细胞分化的负面影响。总之，COX-1有助于NB4细胞的ATRA依赖性成熟，并受As₂O₃影响。这些结果还表明，在接受ATRA和As₂O₃联合治疗的APL患者中应避免使用非甾体抗炎药。
