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Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo

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Abstract

In clinical practice, most patients with non small cell lung cancer (NSCLC) who respond to tyrosine kinase inhibitors eventually progress because of an acquired resistance mutation, T790M, in epidermal growth factor receptor (EGFR). Thus, it is important to identify a new drug to reduce resistance. The aim of this study was to test whether genistein combined with gefitinib is effective against NSCLC in a cell line carrying T790M, and to clarify the underlying mechanisms. The human lung cancer cell line H1975 was used as an in vitro and in vivo model. Cells were treated with gefitinib, genistein, or a combination at a range of concentrations. Cell proliferation was calculated to assess the anticancer effects of the compounds in vitro. Flow cytometry and Western blotting were employed to determine the inhibitory effects on proliferation and the induction of apoptosis. The in vivo effects of the compounds were examined using a xenografted nude mouse model for validation. Gefitinib together with genistein enhanced both growth inhibition and apoptosis; however, the greatest synergistic effect was observed at low concentrations. p-EGFR, p-Akt, and p-mTOR expressions in vitro were reduced more by the combined use of the drugs, whereas caspase-3 and PARP activities were increased. Significantly more tumor growth inhibition was detected following combination treatment in the in vivo model. These findings suggest that genistein enhanced the antitumor effects of gefitinib in a NSCLC cell line carrying the T790M mutation. This synergistic activity may be due to increased inhibition of the downstream molecular and pro-apoptotic effects of EGFR.

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Authors and Affiliations

  1. Department of Child and Adolescent Health, School of Public Health and Tropical Medicine, Southern Medical University, 1023 Southern Shatai Road, Guangzhou, 510515, China

    Hang Zhu & Bing De Luo

  2. Department of Thoracic Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China

    Hua Cheng

  3. School of Public Health, Guilin Medical University, Guilin, China

    Yuan Ren

  4. Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Zhan Guo Liu

  5. Department of Lung Cancer, Cancer Center, Guangdong General Hospital, Southern Medical University, 106 Zhongshan Er Road, Guangzhou, 510080, China

    Yi Fang Zhang

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  1. Hang Zhu
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  3. Yuan Ren
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  4. Zhan Guo Liu
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Correspondence to Yi Fang Zhang or Bing De Luo.

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Hang Zhu and Hua Cheng are contributed equally to this work.

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Zhu, H., Cheng, H., Ren, Y. et al. Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo. Mol Biol Rep 39, 4971–4979 (2012). https://doi.org/10.1007/s11033-011-1293-1

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  • DOI: https://doi.org/10.1007/s11033-011-1293-1

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