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Title: AZD-7648, a DNA-PK Inhibitor, Induces DNA Damage, Apoptosis, and Cell Cycle Arrest in Chronic and Acute Myeloid Leukemia Cells
Authors: Lapa, Beatriz Santos 
Costa, Maria Inês 
Figueiredo, Diana 
Jorge, Joana 
Alves, Raquel 
Monteiro, Ana Raquel 
Serambeque, Beatriz 
Laranjo, Mafalda 
Botelho, Maria Filomena 
Carreira, Isabel Marques 
Sarmento-Ribeiro, Ana Bela 
Gonçalves, Ana Cristina 
Keywords: DNA damage repair; DNA-PK inhibitor; AZD-7648; myeloid leukemia; therapeutic target
Issue Date: 18-Oct-2023
Publisher: MDPI
Project: CIMAGO—Center of Investigation on Environment, Genetics, and Oncobiology, Faculty of Medicine, University of Coimbra 
Sociedade Portuguesa de Hematologia and by Liga Portuguesa Contra o Cancro—Núcleo Regional do Centro 
FCT PhD grant (2020.08261.BD, 2022.10127.BD, 2020.07672.BD and SFRH/BD/145531/2019) 
Serial title, monograph or event: International Journal of Molecular Sciences
Volume: 24
Issue: 20
Abstract: 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 γH2AX 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 µM. 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.
ISSN: 1422-0067
DOI: 10.3390/ijms242015331
Rights: openAccess
Appears in Collections:I&D CIBB - Artigos em Revistas Internacionais
I&D ICBR - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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