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Schedule-dependent cytotoxicity of sunitinib and TRAIL in human non-small cell lung cancer cells with or without EGFR and KRAS mutations

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Background

Non-small cell lung cancer (NSCLC) patients who do initially respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may eventually develop resistance, which may at least partly be due to the acquisition of a secondary EGFR mutation (T790M). Additionally, it has been found that KRAS mutations may serve as poor prognostic biomarkers. Here, we aimed at establishing a suitable treatment regimen for the multi-target TKI sunitinib and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in NSCLC-derived cells with or without EGFR and KRAS mutations.

Methods

Four NSCLC-derived cell lines with or without EGFR and KRAS mutations were exposed to different sunitinib and TRAIL treatment regimens. Alterations in cell viability, cell cycle distribution, apoptosis, phosphorylation of AKT and expression of the death receptors DR4 and DR5 were evaluated using CCK8, flow cytometry and Western blotting assays, respectively.

Results

A synergistic cytotoxic effect was observed in all four cell lines treated with sunitinib (1 nM) followed by TRAIL (100 ng/ml), as well as after simultaneous treatment with both agents. We found that sunitinib enhances TRAIL-induced G0/G1-phase cell cycle arrest and blocks TRAIL-triggered activation of AKT as the underlying mechanism. In contrast, we observed antagonistic effects when sunitinib was administered after TRAIL to the cell lines tested. A decreased DR4 and DR5 expression was found to be correlated with this antagonism.

Conclusion

From our data we conclude that administration of sunitinib followed by TRAIL, as well as a simultaneous administration of both agents, serve as favorable treatment regimens for NSCLC-derived cells, irrespective of their EGFR and/or KRAS mutation status.

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Authors and Affiliations

  1. Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People’s Republic of China

    Yong-Xia Bao

  2. Department of Laboratory, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People’s Republic of China

    Xiao-Dan Zhao

  3. Dental Hospital, The First Affiliated Hospital of Harbin Medical University, 150001, 23 Youzheng Road, Nangang District, Harbin, Heilongjiang, People’s Republic of China

    Hong-Bin Deng & Xing Lu

  4. Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Rd, Harbin, 150081, Heilongjiang, People’s Republic of China

    Chang-Lian Lu

  5. Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People’s Republic of China

    Yang Guo & Li-Li Deng

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  1. Yong-Xia Bao
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Correspondence to Li-Li Deng.

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Grant Support

This study was supported by a research Grant from the Postdoctoral Research Fund (Grant No. LBH-Z12159) provided by the Postdoctoral Management Office of Heilongjiang Province, China, and a research Grant from the Natural Science Foundation of Heilongjiang Province, China (Grant No. H201311) provided by the committee of Natural Science Foundation of Heilongjiang Province. This study was also supported by a research grant from the PhD Research Fund (Grant No. BS2012–16) provided by the Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China. We thank all participants who contributed to in this study.

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Additional information

Yong-Xia Bao and Xiao-Dan Zhao contributed equally to this work.

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Bao, YX., Zhao, XD., Deng, HB. et al. Schedule-dependent cytotoxicity of sunitinib and TRAIL in human non-small cell lung cancer cells with or without EGFR and KRAS mutations. Cell Oncol. 39, 343–352 (2016). https://doi.org/10.1007/s13402-016-0278-4

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