TY - JOUR AB - Leukemia, a malignant hematological disease, has poor therapeutic outcomes due to chemotherapeutic resistance. Increasing evidence has confirmed that the elevated capacity for DNA damage repair in cancer cells is a major mechanism of acquired chemotherapeutic resistance. Thus, combining chemotherapy with inhibitors of DNA damage repair pathways is potentially an ideal strategy for treating leukemia. Checkpoint kinase 1 (CHK1) is an important component of the DNA damage response (DDR) and is involved in the G2/M DNA damage checkpoint. In the present study, we demonstrated that shRNA‑mediated CHK1 silencing suppressed cell proliferation and enhanced the cytotoxic effects of etoposide (VP16) in the chronic myeloid leukemia (CML) cell line K562 through the results of CCK‑8, and comet assay. The results demonstrated that shRNA‑induced CHK1 silencing can override G2/M arrest and impair homologous recombination (HR) repair by reducing breast cancer susceptibility gene 1 (BRCA1) expression. Cells had no time, and thus limited ability, to repair the damage and were thus more sensitive to chemotherapy after CHK1 downregulation. Second, we tested the therapeutic effect of VP16 combined with CCT245737, an orally bioavailable CHK1 inhibitor, and observed strong synergistic anticancer effects in K562 cells. Moreover, we discovered that CCT245737 significantly prevented the G2/M arrest caused by acute exposure to VP16. Interestingly, CCT245737 inhibited both BRCA1 and Rad51, the most important component of the HR repair pathway. In conclusion, these results revealed that CHK1 is potentially an ideal therapeutic target for the treatment of CML and that CCT245737 should be considered a candidate drug. AD - Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, Fujian 361003, P.R. China Department of Pathology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China AU - Fan,Zhuoyi AU - Luo,Huacheng AU - Zhou,Jie AU - Wang,Fangce AU - Zhang,Wenjun AU - Wang,Jian AU - Li,Shuo AU - Lai,Qian AU - Xu,Yueshuang AU - Wang,Guangming AU - Liang,Aibin AU - Xu,Jun DA - 2020/11/01 DO - 10.3892/or.2020.7757 EP - 2164 IS - 5 JO - Oncol Rep KW - CHK1 CCT245737 DNA damage response etoposide chronic myeloid leukemia PY - 2020 SN - 1021-335X 1791-2431 SP - 2152 ST - Checkpoint kinase‑1 inhibition and etoposide exhibit a strong synergistic anticancer effect on chronic myeloid leukemia cell line K562 by impairing homologous recombination DNA damage repair T2 - Oncology Reports TI - Checkpoint kinase‑1 inhibition and etoposide exhibit a strong synergistic anticancer effect on chronic myeloid leukemia cell line K562 by impairing homologous recombination DNA damage repair UR - https://doi.org/10.3892/or.2020.7757 VL - 44 ER -