Dong Hongli, Zitt Christof, Auriga Cornelia, Hatzelmann Armin, Epstein Paul M
Signal Transduction Laboratory, Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-6125, USA.
Biochem Pharmacol. 2010 Feb 1;79(3):321-9. doi: 10.1016/j.bcp.2009.09.001. Epub 2009 Sep 6.
Stimulation of the cAMP signaling pathway has been shown to induce apoptosis and augment the effects of glucocorticoids in inducing apoptosis in leukemic cells. We recently reported that in primary B cell chronic lymphocytic leukemic (B-CLL) cells, apoptosis could be induced by stimulating the cAMP signaling pathway with a phosphodiesterase4 (PDE4) inhibitor alone; while in contrast, in the CEM T leukemic cell line, PDE4 inhibitors alone were ineffective, and concurrent stimulation of adenylyl cyclase was required to see effects [Tiwari et al. (2005)]. We report here that in the CEM and Jurkat T leukemic cell lines, the most abundantly expressed PDEs are PDE3B, PDE4A, PDE4D, PDE7A, and PDE8A. Selective inhibition of PDE3, PDE4 or PDE7 alone produces little effect on cell viability, but inhibition of all three of these PDEs together dramatically enhances glucocorticoid-induced apoptosis in CEM cells, and overcomes glucocorticoid resistance in a glucocorticoid-resistant CEM cell line. These studies indicate that for some leukemic cell types, a desired therapeutic effect may be achieved by inhibiting more than one form of PDE.
环磷酸腺苷（cAMP）信号通路的刺激已被证明可诱导白血病细胞凋亡，并增强糖皮质激素诱导凋亡的作用。我们最近报道，在原发性B细胞慢性淋巴细胞白血病（B-CLL）细胞中，单独使用磷酸二酯酶4（PDE4）抑制剂刺激cAMP信号通路即可诱导凋亡；而相比之下，在CEM T白血病细胞系中，单独使用PDE4抑制剂无效，需要同时刺激腺苷酸环化酶才能看到效果[蒂瓦里等人（2005年）]。我们在此报告，在CEM和Jurkat T白血病细胞系中，表达最丰富的磷酸二酯酶是PDE3B、PDE4A、PDE4D、PDE7A和PDE8A。单独选择性抑制PDE3、PDE4或PDE7对细胞活力影响不大，但同时抑制这三种磷酸二酯酶可显著增强糖皮质激素诱导的CEM细胞凋亡，并克服糖皮质激素耐药性CEM细胞系中的糖皮质激素耐药性。这些研究表明，对于某些白血病细胞类型，通过抑制多种形式的磷酸二酯酶可能实现理想的治疗效果。
