Time-dependent cytotoxicity induced by SJU-136 (NSC 694501): influence of the rate of interstrand cross-link formation on DNA damage signaling
Time-dependent cytotoxicity induced by SJU-136 (NSC 694501): influence of the rate of interstrand cross-link formation on DNA damage signaling
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DOI：
10.1158/1535-7163.mct-06-0018
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发表时间：
2006-06-01
影响因子：
5.7
通讯作者：
Guichard, Sylvie M.
中科院分区：
文献类型：
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作者：
Arnould, Stephanie;Spanswick, Victoria J.;Guichard, Sylvie M.
SJG-136 是一种新型吡咯并苯二氮卓二聚体，可诱导时间依赖性细胞毒性。 HCT 116 细胞暴露于 50 nmol/L SJG-136 1 小时或 1 nmol/L SJG-136 24 小时，以达到相似水平的链间交联 (ICL)。与 24 小时暴露相比，短时间暴露导致 ICL 快速形成（1 小时）、早期 H2AX 灶形成（4 小时）、显着的 S 期停滞以及 Nbs1（丝氨酸 343）和 Chk1（丝氨酸 317）磷酸化程度更高。长时间暴露于低浓度的 SJG-136 会诱导 ICL 的逐渐形成（长达 24 小时），这与有限的 S 期停滞和延迟的 Nbs1 磷酸化有关。长时间暴露还与 p53 丝氨酸 15 和 20 磷酸化减少、丝氨酸 392 磷酸化有限且延迟以及 p21 水平不那么明显增加有关。这些数据表明，与较高浓度的 SJG-136 暴露 1 小时相比，暴露于低浓度的 SJG-136 24 小时导致 DNA 损伤信号传导延迟和减少，从而导致更大的细胞毒性，并有助于 SJG-136 的时间依赖性细胞毒性作用。
SJG-136 is a new pyrrolobenzodiazepine dimer inducing time-dependent cytotoxicity. HCT 116 cells were exposed to 50 nmol/L of SJG-136 for 1 hour or 1 nmol/L of SJG-136 for 24 hours to achieve similar levels of interstrand cross-links (ICL). The short exposure led to a rapid formation of ICLs (1 hour), early H2AX foci formation (4 hours), prominent S phase arrest, and greater phosphorylation of Nbs1 (on serine 343) and Chk1 (on serine 317) than a 24-hour exposure. The prolonged exposure at low concentrations of SJG-136 induced a gradual formation of ICLs (up to 24 hours) which was associated with a limited S phase arrest and delayed Nbs1 phosphorylation. Prolonged exposure was also associated with a reduced phosphorylation of p53 on serines 15 and 20, a limited and delayed phosphorylation on serine 392, and a less prominent increase in p21 levels. These data suggest that the 24-hour exposure to a low concentration of SJG-136 led to delayed and reduced DNA damage signaling compared with a higher concentration of SJG-136 for 1 hour, resulting in greater cytotoxicity and contributing to the time-dependent cytotoxic effect of SJG-136.