MK-8776, a novel Chk1 inhibitor, exhibits an improved radiosensitizing effect compared to UCN-01 by exacerbating radiation-induced aberrant mitosis.
MK-8776, a novel Chk1 inhibitor, exhibits an improved radiosensitizing effect compared to UCN-01 by exacerbating radiation-induced aberrant mitosis.
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DOI：
10.1016/j.tranon.2017.04.002
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发表时间：
2017-08
影响因子：
5
通讯作者：
Inanami O
中科院分区：
文献类型：
--
作者：
Suzuki M;Yamamori T;Bo T;Sakai Y;Inanami O
检查点激酶1 （Chk1）是一种进化上保守的丝氨酸/苏氨酸激酶，在G2/M检查点信号传导中起重要作用。在这里，我们评估了一种新的选择性Chk1抑制剂MK-8776的放射增敏作用，将其与第一代Chk1抑制剂UCN-01的疗效进行了比较，并试图阐明放射增敏的机制。在克隆生存试验中，MK-8776表现出比UCN-01更明显的放射致敏作用，具有更低的细胞毒性。重要的是，MK-8776的放射增敏可以在低至2.5 Gy的剂量下实现，这是临床适用的照射剂量。MK-8776加重了有丝分裂突变（MC）和中心体异常，但不影响DNA双链断裂的修复动力学，UCN-01则没有。此外，活细胞成像显示MK-8776显著消除了辐射诱导的G2/M检查点，延长了有丝分裂期，增强了异常有丝分裂。这表明MK-8776抑制Chk1激活纺锤体组装检查点并增加辐照EMT6细胞的有丝分裂缺陷。总之，我们已经证明，在最低毒性浓度下，MK-8776通过增强异常有丝分裂和MC来增强辐射诱导的细胞死亡，而不影响DNA损伤修复。
Checkpoint kinase 1 (Chk1) is an evolutionarily conserved serine/threonine kinase that plays an important role in G2/M checkpoint signaling. Here, we evaluate the radiosensitizing effects of a novel selective Chk1 inhibitor MK-8776, comparing its efficacy with a first-generation Chk1 inhibitor UCN-01, and attempt to elucidate the mechanism of radiosensitization. In a clonogenic survival assay, MK-8776 demonstrated a more pronounced radiosensitizing effect than UCN-01, with lower cytotoxicity. Importantly, radiosensitization by MK-8776 can be achieved at doses as low as 2.5 Gy, which is a clinically applicable irradiation dose. MK-8776, but not UCN-01, exacerbated mitotic catastrophe (MC) and centrosome abnormalities, without affecting repair kinetics of DNA double strand breaks. Furthermore, live-cell imaging revealed that MK-8776 significantly abrogated the radiation-induced G2/M checkpoint, prolonged the mitotic phase, and enhanced aberrant mitosis. This suggests that Chk1 inhibition by MK-8776 activates a spindle assembly checkpoint and increases mitotic defects in irradiated EMT6 cells. In conclusion, we have shown that, at minimally toxic concentrations, MK-8776 enhances radiation-induced cell death through the enhancement of aberrant mitosis and MC, without affecting DNA damage repair.