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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

  • Authors:
    • Zhuoyi Fan
    • Huacheng Luo
    • Jie Zhou
    • Fangce Wang
    • Wenjun Zhang
    • Jian Wang
    • Shuo Li
    • Qian Lai
    • Yueshuang Xu
    • Guangming Wang
    • Aibin Liang
    • Jun Xu
  • View Affiliations / Copyright

    Affiliations: 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
    Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2152-2164
    |
    Published online on: September 7, 2020
       https://doi.org/10.3892/or.2020.7757
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Abstract

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.
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Copy and paste a formatted citation
Spandidos Publications style
Fan Z, Luo H, Zhou J, Wang F, Zhang W, Wang J, Li S, Lai Q, Xu Y, Wang G, Wang G, et al: 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. Oncol Rep 44: 2152-2164, 2020.
APA
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J. ... Xu, J. (2020). 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. Oncology Reports, 44, 2152-2164. https://doi.org/10.3892/or.2020.7757
MLA
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J., Li, S., Lai, Q., Xu, Y., Wang, G., Liang, A., Xu, J."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". Oncology Reports 44.5 (2020): 2152-2164.
Chicago
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J., Li, S., Lai, Q., Xu, Y., Wang, G., Liang, A., Xu, J."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". Oncology Reports 44, no. 5 (2020): 2152-2164. https://doi.org/10.3892/or.2020.7757
Copy and paste a formatted citation
x
Spandidos Publications style
Fan Z, Luo H, Zhou J, Wang F, Zhang W, Wang J, Li S, Lai Q, Xu Y, Wang G, Wang G, et al: 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. Oncol Rep 44: 2152-2164, 2020.
APA
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J. ... Xu, J. (2020). 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. Oncology Reports, 44, 2152-2164. https://doi.org/10.3892/or.2020.7757
MLA
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J., Li, S., Lai, Q., Xu, Y., Wang, G., Liang, A., Xu, J."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". Oncology Reports 44.5 (2020): 2152-2164.
Chicago
Fan, Z., Luo, H., Zhou, J., Wang, F., Zhang, W., Wang, J., Li, S., Lai, Q., Xu, Y., Wang, G., Liang, A., Xu, J."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". Oncology Reports 44, no. 5 (2020): 2152-2164. https://doi.org/10.3892/or.2020.7757
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