Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532
Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532
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DOI：
10.1182/blood-2003-12-4322
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发表时间：
2005-02-15
期刊：
影响因子：
20.3
通讯作者：
Martens, UM
中科院分区：
文献类型：
--
作者：
El-Daly, H;Kull, M;Martens, UM
端粒酶是基于机制的治疗方法的一个有吸引力的靶点，因为它的激活与大多数癌细胞的无限增殖有关。最近，一种非核苷类小分子抑制剂BIBR1532(2-[(E)-3-萘甲烯-2-基-2-烯-氨基]-苯甲酸)被鉴定出来，它对端粒酶的抑制具有高度的选择性，导致肿瘤细胞的延迟生长停滞。在短期培养试验中，我们观察了BIBR1532在不同白血病细胞系以及急性髓系白血病(AML)和慢性淋巴细胞白血病(CLL)患者原代细胞中的作用。我们观察到在30到80微米的浓度范围内，BIBR1532具有剂量依赖性的直接细胞毒性。有趣的是，细胞死亡并不依赖于端粒酶的催化活性，而是在端粒很长的细胞中延迟。我们观察到依赖于时间的个体端粒侵蚀，这与端粒重复序列结合因子2(TRF2)的缺失和P53的磷酸化增加有关。重要的是，来自脐带血和白细胞采集样本的正常CD34(+)细胞的增殖能力不受BIBR1532治疗的影响。我们的结论是，在较高浓度下使用这类端粒酶抑制物对造血系统的恶性细胞产生直接的细胞毒作用，这似乎源于对单个端粒结构的直接破坏，必须从端粒酶抑制的整体端粒缩短中剥离出来。(C)2005年，由美国血液病学会提供。
Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a nonnucleosidic small molecule inhibitor, BIBR1532 (2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]- benzoic acid), has been identified that is highly selective for Inhibition of telomerase, resulting in delayed growth arrest of tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in short-term culture assays We observed a dose-dependent direct cytotoxicity in concentrations ranging from 30 to 80 muM. Interestingly, cell death was not dependent on the catalytic activity of telomerase but was delayed in cells with very long telomeres. We observed time-dependent individual telomere, erosion, which was associated with loss of telomeric repeat binding factor 2 (TRF2) and increased phosphorylation of p53. Importantly, the proliferative capacity of normal CD34(+) cells from cord blood and leukapheresis samples was not affected by treatment with BIBR1532. We conclude that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system, which appears to derive from direct damage of the structure of individual telomeres and must be dissected from telomerase-suppressed overall telomere shortening. (C) 2005 by The American Society of Hematology.