MK-8776, a novel Chk1 inhibitor, exhibits an improved radiosensitizing effect compared to UCN-01 by exacerbating radiation-induced aberrant mitosis. Suzuki, M., Yamamori, T., Bo, T., Sakai, Y., & Inanami, O. Translational Oncology, 10(4):491–500, May, 2017. Paper doi abstract bibtex 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.
@article{suzuki_mk-8776_2017,
title = {{MK}-8776, a novel {Chk1} inhibitor, exhibits an improved radiosensitizing effect compared to {UCN}-01 by exacerbating radiation-induced aberrant mitosis},
volume = {10},
issn = {1936-5233},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447387/},
doi = {10.1016/j.tranon.2017.04.002},
abstract = {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.},
number = {4},
urldate = {2017-10-18},
journal = {Translational Oncology},
author = {Suzuki, Motofumi and Yamamori, Tohru and Bo, Tomoki and Sakai, Yuri and Inanami, Osamu},
month = may,
year = {2017},
pmid = {28550769},
pmcid = {PMC5447387},
pages = {491--500},
}
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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.","number":"4","urldate":"2017-10-18","journal":"Translational Oncology","author":[{"propositions":[],"lastnames":["Suzuki"],"firstnames":["Motofumi"],"suffixes":[]},{"propositions":[],"lastnames":["Yamamori"],"firstnames":["Tohru"],"suffixes":[]},{"propositions":[],"lastnames":["Bo"],"firstnames":["Tomoki"],"suffixes":[]},{"propositions":[],"lastnames":["Sakai"],"firstnames":["Yuri"],"suffixes":[]},{"propositions":[],"lastnames":["Inanami"],"firstnames":["Osamu"],"suffixes":[]}],"month":"May","year":"2017","pmid":"28550769","pmcid":"PMC5447387","pages":"491–500","bibtex":"@article{suzuki_mk-8776_2017,\n\ttitle = {{MK}-8776, a novel {Chk1} inhibitor, exhibits an improved radiosensitizing effect compared to {UCN}-01 by exacerbating radiation-induced aberrant mitosis},\n\tvolume = {10},\n\tissn = {1936-5233},\n\turl = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447387/},\n\tdoi = {10.1016/j.tranon.2017.04.002},\n\tabstract = {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.},\n\tnumber = {4},\n\turldate = {2017-10-18},\n\tjournal = {Translational Oncology},\n\tauthor = {Suzuki, Motofumi and Yamamori, Tohru and Bo, Tomoki and Sakai, Yuri and Inanami, Osamu},\n\tmonth = may,\n\tyear = {2017},\n\tpmid = {28550769},\n\tpmcid = {PMC5447387},\n\tpages = {491--500},\n}\n\n","author_short":["Suzuki, M.","Yamamori, T.","Bo, T.","Sakai, Y.","Inanami, O."],"key":"suzuki_mk-8776_2017","id":"suzuki_mk-8776_2017","bibbaseid":"suzuki-yamamori-bo-sakai-inanami-mk8776anovelchk1inhibitorexhibitsanimprovedradiosensitizingeffectcomparedtoucn01byexacerbatingradiationinducedaberrantmitosis-2017","role":"author","urls":{"Paper":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447387/"},"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://bibbase.org/zotero/tplas","dataSources":["YLgywGcXWx96vKKaB"],"keywords":[],"search_terms":["8776","novel","chk1","inhibitor","exhibits","improved","radiosensitizing","effect","compared","ucn","exacerbating","radiation","induced","aberrant","mitosis","suzuki","yamamori","bo","sakai","inanami"],"title":"MK-8776, a novel Chk1 inhibitor, exhibits an improved radiosensitizing effect compared to UCN-01 by exacerbating radiation-induced aberrant mitosis","year":2017}