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Article

Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation

  • Authors:
    • Sang Eun Park
    • Dong Eun Kim
    • Mi Joung Kim
    • Jee Suk Lee
    • Jin Kyung Rho
    • Seong‑Yun Jeong
    • Eun Kyung Choi
    • Choung‑Soo Kim
    • Jung Jin Hwang
  • View Affiliations / Copyright

    Affiliations: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea, Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
  • Pages: 525-533
    |
    Published online on: October 22, 2018
       https://doi.org/10.3892/or.2018.6814
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Abstract

Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) have been reported in non‑small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR‑activating mutation (EGFR exon 19 deletion) and gefitinib‑resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4‑(2‑aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co‑treatment as well as the cleavage of caspase‑3, caspase‑8, and caspase‑9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co‑treatment with vorinostat and gefitinib induced ROS‑dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR‑TKI to reverse EGFR‑TKI resistance in NSCLC.
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Copy and paste a formatted citation
Spandidos Publications style
Park SE, Kim DE, Kim MJ, Lee JS, Rho JK, Jeong SY, Choi EK, Kim CS and Hwang JJ: Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation. Oncol Rep 41: 525-533, 2019.
APA
Park, S.E., Kim, D.E., Kim, M.J., Lee, J.S., Rho, J.K., Jeong, S. ... Hwang, J.J. (2019). Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation. Oncology Reports, 41, 525-533. https://doi.org/10.3892/or.2018.6814
MLA
Park, S. E., Kim, D. E., Kim, M. J., Lee, J. S., Rho, J. K., Jeong, S., Choi, E. K., Kim, C., Hwang, J. J."Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation". Oncology Reports 41.1 (2019): 525-533.
Chicago
Park, S. E., Kim, D. E., Kim, M. J., Lee, J. S., Rho, J. K., Jeong, S., Choi, E. K., Kim, C., Hwang, J. J."Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation". Oncology Reports 41, no. 1 (2019): 525-533. https://doi.org/10.3892/or.2018.6814
Copy and paste a formatted citation
x
Spandidos Publications style
Park SE, Kim DE, Kim MJ, Lee JS, Rho JK, Jeong SY, Choi EK, Kim CS and Hwang JJ: Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation. Oncol Rep 41: 525-533, 2019.
APA
Park, S.E., Kim, D.E., Kim, M.J., Lee, J.S., Rho, J.K., Jeong, S. ... Hwang, J.J. (2019). Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation. Oncology Reports, 41, 525-533. https://doi.org/10.3892/or.2018.6814
MLA
Park, S. E., Kim, D. E., Kim, M. J., Lee, J. S., Rho, J. K., Jeong, S., Choi, E. K., Kim, C., Hwang, J. J."Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation". Oncology Reports 41.1 (2019): 525-533.
Chicago
Park, S. E., Kim, D. E., Kim, M. J., Lee, J. S., Rho, J. K., Jeong, S., Choi, E. K., Kim, C., Hwang, J. J."Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation". Oncology Reports 41, no. 1 (2019): 525-533. https://doi.org/10.3892/or.2018.6814
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