Petrella Antonello, D'Acunto Cosimo Walter, Rodriquez Manuela, Festa Michela, Tosco Alessandra, Bruno Ines, Terracciano Stefania, Taddei Maurizio, Paloma Luigi Gomez, Parente Luca
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, Fisciano, Salerno, Italy.
Eur J Cancer. 2008 Mar;44(5):740-9. doi: 10.1016/j.ejca.2008.01.023. Epub 2008 Mar 4.
FR235222, a novel histone deacetylase inhibitor (HDACi), at 50nM caused accumulation of acetylated histone H4, inhibition of cell proliferation and G1 cycle arrest accompanied by increase of p21 and down-regulation of cyclin E in human promyelocytic leukaemia U937 cells. The compound was also able to increase the protein and mRNA levels of annexin A1 (ANXA1) without effects on apoptosis. Similar effects were observed in human chronic myelogenous leukaemia K562 cells and human T cell leukaemia Jurkat cells. Cycle arrest and ANXA1 expression, without significant effects on apoptosis, were also induced by different HDACi like suberoylanilide hydroxamic acid (SAHA) and trichostatin-A (TSA). FR235222 at 0.5 microM stimulated apoptosis of all leukaemia cell lines associated to an increased expression of the full-length (37kDa) protein and the appearance of a 33kDa N-terminal cleavage product in both cytosol and membrane. These results suggest that ANXA1 expression may mediate cycle arrest induced by low doses FR235222, whereas apoptosis induced by high doses FR235222 is associated to ANXA1 processing.
新型组蛋白去乙酰化酶抑制剂（HDACi）FR235222在50纳摩尔浓度时，可导致人早幼粒细胞白血病U937细胞中乙酰化组蛋白H4的积累、细胞增殖的抑制以及G1期阻滞，同时伴有p21的增加和细胞周期蛋白E的下调。该化合物还能够增加膜联蛋白A1（ANXA1）的蛋白质和mRNA水平，而对细胞凋亡没有影响。在人慢性粒细胞白血病K562细胞和人T细胞白血病Jurkat细胞中也观察到了类似的效应。不同的HDACi如辛二酰苯胺异羟肟酸（SAHA）和曲古抑菌素A（TSA）也可诱导细胞周期阻滞和ANXA1表达，且对细胞凋亡无显著影响。0.5微摩尔浓度的FR235222可刺激所有白血病细胞系的凋亡，这与全长（37千道尔顿）蛋白表达的增加以及胞质和膜中33千道尔顿N端裂解产物的出现有关。这些结果表明，ANXA1的表达可能介导低剂量FR235222诱导的细胞周期阻滞，而高剂量FR235222诱导的细胞凋亡与ANXA1的加工有关。
