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Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer

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Abstract

Purpose

Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer.

Methods

MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model.

Results

The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone.

Conclusions

The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.

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Acknowledgements

This study was supported by the Grant from National Natural Science Foundation of China (no. 81202447 and no. 81373135), the Programs for Science and Technology Development of Henan (no. 172102310502), and the Support Project for Talents of Science and Technology Innovation in Universities of Henan (no. 15HASTIT040).

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Author notes

  1. Xiao-fang Guo and Sai-sai Li contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453003, Henan, People’s Republic of China

    Xiao-fang Guo, Sai-sai Li & Qiao-hua Dou

  2. Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, People’s Republic of China

    Xiao-fei Zhu

  3. Henan Collaborative Innovation center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, People’s Republic of China

    Xiao-fei Zhu

  4. Department of Gynecology and Obstetrics, Third Affiliated Hospital, Zhengzhou University, Zhengzhou, People’s Republic of China

    Duan Liu

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  1. Xiao-fang Guo
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Correspondence to Xiao-fang Guo.

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Guo, Xf., Li, Ss., Zhu, Xf. et al. Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer. Cancer Chemother Pharmacol 82, 383–394 (2018). https://doi.org/10.1007/s00280-018-3627-3

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