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Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC

  • Authors:
    • Chi Pan
    • Huijie Duan
    • Yinan Wu
    • Chunpeng Zhu
    • Chenghao Yi
    • Yin Duan
    • Demin Lu
    • Cheng Guo
    • Deqi Wu
    • Yanyan Wang
    • Xianhua Fu
    • Jing Xu
    • Yiding Chen
    • Meng Luo
    • Wei Tian
    • Tao Pan
    • Wenhong Xu
    • Suzhan Zhang
    • Jianjin Huang
  • View Affiliations / Copyright

    Affiliations: Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Cancer Institute (National Ministry of Education Key Laboratory of Cancer Prevention and Intervention), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Breast Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Breast Surgery, The Zhejiang Provincial Hospital of Traditional Chinese Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China, Department of Gastrointestinal Thyroid and Breast Surgery, The Shulan (Hangzhou) Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
    Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 939-955
    |
    Published online on: July 27, 2020
       https://doi.org/10.3892/ijo.2020.5103
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Abstract

Lung cancer has the highest incidence and mortality rates among the malignant tumor types worldwide. Platinum‑based chemotherapy is the main treatment for advanced non‑small‑cell lung cancer (NSCLC), and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) have greatly improved the survival of patients with EGFR‑sensitive mutations. However, there is no standard therapy for treating patients who are EGFR‑TKI resistant. Combining EGFR‑TKIs and platinum‑based chemotherapy is the most popular strategy in the clinical practice. However, the synergistic mechanism between EGFR‑TKIs and platinum remains unknown. Therefore, the aim of the present study was to determine the synergistic mechanism of gefitinib (an EGFR‑TKI) and cisplatin (a main platinum‑based drug). MTT assay, apoptosis analysis, tumorsphere formation and an orthotropic xenograft mouse model were used to examine the combination effects of gefitinib and cisplatin on NSCLC. Co‑immunoprecipitation and immunofluorescence were used to identify the underlying mechanism. It was found that gefitinib could selectively inhibit EGFR from entering the nucleus, decrease DNA‑PK activity and enhance the cytotoxicity of cisplatin on NSCLC. Collectively, the results suggested that inhibition of DNA‑dependent protein kinase by gefitinib may be due to the synergistic mechanism between gefitinib and cisplatin. Thus, the present study provides a novel insight into potential biomarkers for the selection of combination therapy of gefitinib and cisplatin.
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Copy and paste a formatted citation
Spandidos Publications style
Pan C, Duan H, Wu Y, Zhu C, Yi C, Duan Y, Lu D, Guo C, Wu D, Wang Y, Wang Y, et al: Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. Int J Oncol 57: 939-955, 2020.
APA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y. ... Huang, J. (2020). Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. International Journal of Oncology, 57, 939-955. https://doi.org/10.3892/ijo.2020.5103
MLA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57.4 (2020): 939-955.
Chicago
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57, no. 4 (2020): 939-955. https://doi.org/10.3892/ijo.2020.5103
Copy and paste a formatted citation
x
Spandidos Publications style
Pan C, Duan H, Wu Y, Zhu C, Yi C, Duan Y, Lu D, Guo C, Wu D, Wang Y, Wang Y, et al: Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. Int J Oncol 57: 939-955, 2020.
APA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y. ... Huang, J. (2020). Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC. International Journal of Oncology, 57, 939-955. https://doi.org/10.3892/ijo.2020.5103
MLA
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57.4 (2020): 939-955.
Chicago
Pan, C., Duan, H., Wu, Y., Zhu, C., Yi, C., Duan, Y., Lu, D., Guo, C., Wu, D., Wang, Y., Fu, X., Xu, J., Chen, Y., Luo, M., Tian, W., Pan, T., Xu, W., Zhang, S., Huang, J."Inhibition of DNA‑PK by gefitinib causes synergism between gefitinib and cisplatin in NSCLC". International Journal of Oncology 57, no. 4 (2020): 939-955. https://doi.org/10.3892/ijo.2020.5103
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