Department of Hematology and Rheumatology, Itabashi Hospital, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
Oncol Rep. 2012 Nov;28(5):1875-82. doi: 10.3892/or.2012.2006. Epub 2012 Aug 31.
The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 µM) and apoptosis at high concentrations (1-2 µM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 µM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 µM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.
三氧化二砷（ATO）、全反式维甲酸（ATRA）和粒细胞集落刺激因子（G-CSF）单独或联合作用对急性早幼粒细胞白血病（APL）细胞系 HT93A 的分化、生长抑制和砷摄取的影响进行了研究。ATO 在低浓度（0.125 µM）下诱导分化，在高浓度（1-2 µM）下诱导凋亡。此外，ATRA 诱导的分化作用强于 ATO。ATRA 和 ATO 之间没有协同作用。G-CSF 促进了 ATO 和 ATRA 的分化诱导活性。ATRA 和 G-CSF 的组合显示出最大的分化作用，而添加 ATO 则没有益处。与单独使用 ATO 相比，添加 1 µM ATRA 和/或 50 ng/ml G-CSF 对凋亡没有影响。ATRA 以时间和剂量依赖的方式诱导水通道蛋白-9（AQP9）的表达，AQP9 是一种跨膜转运体，被认为是砷摄取的主要途径。然而，与对照组相比，用 1 µM ATRA 处理会使砷摄取减少 43.7%。尽管 G-CSF 的添加不会增强细胞中 AQP9 的表达，但减少的砷摄取会恢复到与对照组相同的水平。ATRA 降低细胞活力，与单独用 ATRA 处理相比，向 ATRA 中添加 50 ng/ml G-CSF 可显著增加存活细胞的数量。G-CSF 不仅促进了 ATRA 和 ATO 的分化诱导活性，而且使 APL 细胞容易增加砷摄取。这些观察结果为使用这三种药物联合治疗 APL 提供了新的见解。
