Dose dependent effects on cell cycle checkpoints and DNA repair by bendamustine.
Dose dependent effects on cell cycle checkpoints and DNA repair by bendamustine.
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DOI：
10.1371/journal.pone.0040342
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yen TJ
中科院分区：
文献类型：
--
作者：
Beeharry N;Rattner JB;Bellacosa A;Smith MR;Yen TJ
苯达莫司汀（BDM）是一种活性化疗药物，在美国获得批准。S.用于治疗慢性淋巴细胞白血病和非霍奇金淋巴瘤。其化学结构表明其可能具有烷化剂和抗代谢活性;然而，确切的作用机制尚不清楚。本文报道了BDM对HeLa细胞的细胞周期、DNA损伤、检查点反应和细胞死亡的浓度依赖性影响。低浓度的BDM将细胞短暂地阻滞在G2期，而高出4倍的浓度将细胞阻滞在S期。处理48小时后，50 µM而非200 µM的DNA损伤得到有效修复，表明两种浓度下的DNA修复效率存在差异。事实上，干扰碱基切除修复使细胞对较低浓度的BDM敏感。对BDM的检查点反应的时间推移研究表明，抑制Chk 1导致S-和G2-停滞细胞过早进入有丝分裂。然而，尽管在G2期（低剂量BDM）停滞的细胞进入有丝分裂，分离它们的染色体并正常分裂，S期停滞的细胞（高剂量BDM）表现出高度异常的有丝分裂，由此EM图像显示高度碎片化的染色体。这些细胞中的绝大多数在没有退出有丝分裂的情况下死亡。抑制Chk 1依赖的DNA损伤检查点加速了BDM的杀伤时间。我们的研究表明，BDM可能会影响不同的生物过程，这取决于药物浓度。可以通过抑制碱基切除修复或破坏DNA损伤检查点途径来使细胞对BDM的杀伤敏感。
Bendamustine (BDM) is an active chemotherapeutic agent approved in the U. S. for treating chronic lymphocytic leukemia and non-Hodgkin lymphoma. Its chemical structure suggests it may have alkylator and anti-metabolite activities; however the precise mechanism of action is not well understood. Here we report the concentration-dependent effects of BDM on cell cycle, DNA damage, checkpoint response and cell death in HeLa cells. Low concentrations of BDM transiently arrested cells in G2, while a 4-fold higher concentration arrested cells in S phase. DNA damage at 50, but not 200 µM, was efficiently repaired after 48 h treatment, suggesting a difference in DNA repair efficiency at the two concentrations. Indeed, perturbing base-excision repair sensitized cells to lower concentrations of BDM. Timelapse studies of the checkpoint response to BDM showed that inhibiting Chk1 caused both the S- and G2-arrested cells to prematurely enter mitosis. However, whereas the cells arrested in G2 (low dose BDM) entered mitosis, segregated their chromosomes and divided normally, the S-phase arrested cells (high dose BDM) exhibited a highly aberrant mitosis, whereby EM images showed highly fragmented chromosomes. The vast majority of these cells died without ever exiting mitosis. Inhibiting the Chk1-dependent DNA damage checkpoint accelerated the time of killing by BDM. Our studies suggest that BDM may affect different biological processes depending on drug concentration. Sensitizing cells to killing by BDM can be achieved by inhibiting base-excision repair or disrupting the DNA damage checkpoint pathway.
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DOI：
10.1007/s00432-007-0278-x
发表时间：
2008-02-01
影响因子：
3.6
作者：
Gaul, Leander;Mandl-Weber, Sonja;Schmidmaier, Ralf
通讯作者：
Schmidmaier, Ralf
影响因子：
64.8
作者：
JOHNSON, RT;RAO, PN
通讯作者：
RAO, PN
影响因子：
5.7
作者：
Ogura, Michinori;Uchida, Toshiki;Tobinai, Kensei
通讯作者：
Tobinai, Kensei
影响因子：
3.6
作者：
Leoni, Lorenzo M.;Hartley, John A.
通讯作者：
Hartley, John A.
影响因子：
11.5
作者：
Leoni, Lorenzo M.;Bailey, Brandi;Niemeyer, Christina C.
通讯作者：
Niemeyer, Christina C.