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Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}]},{"name":"Centre for Innovative Biomedicine and Biotechnology (CIBB) and the Institute for Clinical and Biomedical Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal","award":["2020.08261.BD"],"award-info":[{"award-number":["2020.08261.BD"]}]},{"name":"Centre for Innovative Biomedicine and Biotechnology (CIBB) and the Institute for Clinical and Biomedical Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal","award":["2022.10127.BD"],"award-info":[{"award-number":["2022.10127.BD"]}]},{"name":"Centre for Innovative Biomedicine and Biotechnology (CIBB) and the Institute for Clinical and Biomedical Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal","award":["2020.07672.BD"],"award-info":[{"award-number":["2020.07672.BD"]}]},{"name":"Centre for Innovative Biomedicine and Biotechnology (CIBB) and the Institute for Clinical and Biomedical Research (iCBR) are supported by the Foundation for Science and Technology (FCT), Portugal","award":["SFRH\/BD\/145531\/2019"],"award-info":[{"award-number":["SFRH\/BD\/145531\/2019"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-007440"],"award-info":[{"award-number":["POCI-01-0145-FEDER-007440"]}]},{"name":"FCT","award":["UID\/NEU\/04539\/2019"],"award-info":[{"award-number":["UID\/NEU\/04539\/2019"]}]},{"name":"FCT","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"FCT","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}]},{"name":"FCT","award":["2020.08261.BD"],"award-info":[{"award-number":["2020.08261.BD"]}]},{"name":"FCT","award":["2022.10127.BD"],"award-info":[{"award-number":["2022.10127.BD"]}]},{"name":"FCT","award":["2020.07672.BD"],"award-info":[{"award-number":["2020.07672.BD"]}]},{"name":"FCT","award":["SFRH\/BD\/145531\/2019"],"award-info":[{"award-number":["SFRH\/BD\/145531\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The non-homologous end joining pathway is vital for repairing DNA double-strand breaks (DSB), with DNA-dependent protein kinase (DNA-PK) playing a critical role. Altered DNA damage response (DDR) in chronic (CML) and acute myeloid leukemia (AML) offers potential therapeutic opportunities. We studied the therapeutic potential of AZD-7648 (DNA-PK inhibitor) in CML and AML cell lines. This study used two CML (K-562 and LAMA-84) and five AML (HEL, HL-60, KG-1, NB-4, and THP-1) cell lines. DDR gene mutations were obtained from the COSMIC database. The copy number and methylation profile were evaluated using MS-MLPA and DDR genes, and telomere length using qPCR. p53 protein expression was assessed using Western Blot, chromosomal damage through cytokinesis-block micronucleus assay, and \u03b3H2AX levels and DSB repair kinetics using flow cytometry. Cell density and viability were analyzed using trypan blue assay after treatment with AZD-7648 in concentrations ranging from 10 to 200 \u00b5M. Cell death, cell cycle distribution, and cell proliferation rate were assessed using flow cytometry. The cells displayed different DNA baseline damage, DDR gene expressions, mutations, genetic\/epigenetic changes, and p53 expression. Only HEL cells displayed inefficient DSB repair. The LAMA-84, HEL, and KG-1 cells were the most sensitive to AZD-7648, whereas HL-60 and K-562 showed a lower effect on density and viability. Besides the reduction in cell proliferation, AZD-7648 induced apoptosis, cell cycle arrest, and DNA damage. In conclusion, these results suggest that AZD-7648 holds promise as a potential therapy for myeloid leukemias, however, with variations in drug sensitivity among tested cell lines, thus supporting further investigation to identify the specific factors influencing sensitivity to this DNA-PK inhibitor.<\/jats:p>","DOI":"10.3390\/ijms242015331","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T02:54:43Z","timestamp":1697684083000},"page":"15331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["AZD-7648, a DNA-PK Inhibitor, Induces DNA Damage, Apoptosis, and Cell Cycle Arrest in Chronic and Acute Myeloid Leukemia Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-4970","authenticated-orcid":false,"given":"Beatriz Santos","family":"Lapa","sequence":"first","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"}]},{"given":"Maria In\u00eas","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"}]},{"given":"Diana","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-8077","authenticated-orcid":false,"given":"Joana","family":"Jorge","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2599-6433","authenticated-orcid":false,"given":"Raquel","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"}]},{"given":"Ana Raquel","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Beatriz","family":"Serambeque","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0689-6007","authenticated-orcid":false,"given":"Mafalda","family":"Laranjo","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-1650","authenticated-orcid":false,"given":"Maria Filomena","family":"Botelho","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Isabel Marques","family":"Carreira","sequence":"additional","affiliation":[{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Cytogenetics and Genomics Laboratory, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4142-4841","authenticated-orcid":false,"given":"Ana Bela","family":"Sarmento-Ribeiro","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), 3000-061 Coimbra, Portugal"},{"name":"Hematology Service, Centro Hospitalar e Universit\u00e1rio de Coimbra (CHUC), 3000-061 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-4802","authenticated-orcid":false,"given":"Ana Cristina","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Oncobiology and Hematology (LOH), University Clinics of Hematology and Oncology, Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Clinical and Biomedical Research (iCBR), Group of Environmental Genetics of Oncobiology (CIMAGO), Faculty of Medicine (FMUC), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"Clinical 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