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Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein

  • Research Article
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Tumor Biology

Abstract

Currently, unresectable esophageal squamous cell carcinoma (ESCC) is primarily treated by chemoradiotherapy. However, the outcome has not improved significantly due to radioresistance of cancer cells. This study aimed to determine the radiosensitizing effect of LCL161, a novel second mitochondrial-derived activator of caspase (Smac) mimetic, in ESCC cells. ESCC cell lines were treated with LCL161 or radiation, alone or in combination. Cell proliferation was detected by MTT assay. Radiosensitization was evaluated by clonogenic survival assay. Cell apoptosis was detected by flow cytometry. The results showed that LCL161 potently sensitized ESCC cells to radiation with a sensitization enhancement ratio of 1.4–2.0. LCL161 increased radiation-induced DNA double-stranded breaks and promoted the apoptosis of ESCC cells, which could be abrogated by a pan-caspase inhibitor z-VAD-FMK. Furthermore, LCL161 decreased the level of cIAP1 in ESCC cells in a dose-dependent manner and synthesized with irradiation to promote the activation of caspase 8 and the upregulation of TNFα expression in ESCC cells. In conclusion, LCL161 acts as a strong radiosensitizer in human esophageal cancer cells by inhibiting the expression of cIAP1 and promoting the activation of caspase 8, leading to enhanced apoptosis.

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Acknowledgments

This work was supported by funds from the Natural Science Foundation of China (no. 81272504), the Innovation Team (no. LJ201123), Jiangsu Provincial Natural Science Fund (no. BK2011854), “333” Project of Jiangsu Province (no. BRA2012210/RS12), and the College Graduates Research and Innovation Program of Jiangsu Province (no. JX22013238).

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Authors and Affiliations

  1. Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Qin Qin, Xi Yang, Jing Lu, Liangliang Zhan, Liping Xu, Chi Zhang, Hongcheng Zhu, Jia Liu, Zheming Liu & Xinchen Sun

  2. Department of Radiation Oncology, The No.1 People’s Hospital of Zhang Jiagang, Zhang Jiagang, China

    Yun Zuo

  3. Department of Radiation Oncology, The No.1 People’s Hospital of Huai’an, Huai’an, China

    Guangzhou Tao

  4. Department of Radiation Oncology, People’s Hospital of Tai Zhou, Taizhou, China

    Shengbin Dai

  5. Department of Radiation Oncology, Subei People’s Hospital, Yangzhou, China

    Xizhi Zhang

  6. Department of Radiation Oncology, The No.2 People’s Hospital of Lian Yungang, Lianyungang, China

    Jianxin Ma

  7. Nantong Tumor Hospital, Nantong, China

    Jing Cai

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  1. Qin Qin
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  2. Yun Zuo
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  3. Xi Yang
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  9. Jia Liu
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  11. Guangzhou Tao
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  13. Xizhi Zhang
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  14. Jianxin Ma
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  16. Xinchen Sun
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Corresponding author

Correspondence to Xinchen Sun.

Additional information

Qin Qin and Yun Zuo contributed equally to this work.

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Qin, Q., Zuo, Y., Yang, X. et al. Smac mimetic compound LCL161 sensitizes esophageal carcinoma cells to radiotherapy by inhibiting the expression of inhibitor of apoptosis protein. Tumor Biol. 35, 2565–2574 (2014). https://doi.org/10.1007/s13277-013-1338-2

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  • DOI: https://doi.org/10.1007/s13277-013-1338-2

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