AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells:: interference with the Akt/NF-κB survival pathway
AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells:: interference with the Akt/NF-κB survival pathway
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DOI：
10.1038/sj.leu.2403679
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发表时间：
2005-04-01
期刊：
影响因子：
11.4
通讯作者：
Garcia-Pardo, A
中科院分区：
文献类型：
--
作者：
Escobar-Díaz, E;López-Martín, EM;Garcia-Pardo, A
B细胞慢性淋巴细胞白血病（B-CLL）的临床治疗受到大多数药物对恶性细胞的进行性耐药和非选择性的限制。缩肽存在于某些细菌中，并显示出有效的抗肿瘤活性。我们已经研究了来自粘质沙雷氏菌的新型环缩肽AT 514（serratamidase）对B-CLL细胞活力的影响。AT 514诱导来自所研究的21名患者的B-CLL细胞凋亡，如通过Annexin-V结合和核凝聚所证实的，平均IC 50为13 μ M。AT 514对氟达拉滨耐药的B-CLL患者有效，对正常PBL无影响。AT 514优先激活内源性凋亡途径，表现为线粒体膜电位丧失、细胞色素c释放以及caspase-9和caspase-3激活，但不激活caspase-8。重要的是，AT 514干扰磷脂酰肌醇-3激酶和蛋白激酶C存活信号，因为它增加了LY 294002和BisI抑制剂的凋亡作用，并诱导Akt在Ser 473处去磷酸化。AT 514还通过显著降低B-CLL中的p65水平来降低NF-κ B活性。这在使用NF-κ B-luc转染的Raji细胞和转基因小鼠的功能测定中得到证实。我们的研究结果表明，AT 514诱导原代B-CLL细胞凋亡，并可能是有用的，这种恶性肿瘤的临床治疗。
Clinical treatment of B-cell chronic lymphocytic leukemia (B-CLL) is limited by the progressive drug resistance and nonselectivity of most drugs towards malignant cells. Depsipeptides are present in certain bacteria and display potent antitumor activity. We have studied the effect of the novel cyclodepsipeptide AT514 ( serratamolide) from Serratia marcescens on B-CLL cell viability. AT514 induced apoptosis of B-CLL cells from the 21 patients studied, as confirmed by Annexin-V binding and nuclei condensation, with an average IC50 of 13 mu M. AT514 was effective in those B-CLL cases resistant to fludarabine, but had no effect on normal PBL. AT514 preferentially activated the intrinsic apoptotic pathway, as evidenced by loss of mitochondrial membrane potential, release of cytochrome c and activation of caspase-9 and -3, but not of caspase-8. Importantly, AT514 interfered with phosphatidylinositol-3 kinase and protein kinase C survival signals since it increased the apoptotic effect of LY294002 and BisI inhibitors, and induced Akt dephosphorylation at Ser 473. AT514 also decreased NF-kappa B activity by dramatically reducing the levels of p65 in B-CLL. This was confirmed on functional assays using NF-kappa B-luc-transfected Raji cells and transgenic mice. Our results establish that AT514 induces apoptosis of primary B-CLL cells and could be useful for clinical treatment of this malignancy.