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Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy

Tumor Biology volume 37, pages 331–339 (2016)Cite this article

Abstract

Acquisition of cisplatin resistance is the common and critical limitation for hepatocellular carcinoma (HCC) therapy. Our study was aimed to determine whether there were conditions under which the addition of imperatorin would reverse the resistance of HCC cells to cisplatin-based therapy. In this study, we found that addition of imperatorin significantly enhanced the cytotoxicity of cisplatin to HCC cells. Since the Mcl-1 was overexpressed in HCC cell lines (HepG2, HepG3B, PLC, Huh7) compared with normal liver cell line (L-O2), we found that the Mcl-1 expression was downregulated by imperatorin but not influenced by cisplatin in HCC cells. In addition, our results showed the combination of imperatorin and cisplatin induced apoptosis and ∆Ψm collapse more significantly compared with treatment of imperatorin or cisplatin alone. Furthermore, the imperatorin-induced sensitization for cisplatin-cytotoxicity to HCC cells was abolished by the transfection of Mcl-1 expression plasmid. Finally, we found that the addition of imperatorin significantly reversed the resistance to cisplatin in cisplatin-resistant HCC cells, which was Mcl-1 dependent. In summary, our study revealed that combination with imperatorin could enhance the antitumor activity of cisplatin via targeting Mcl-1 and reverse the resistance to cisplatin in HCC.

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Acknowledgments

This work was supported by the Program of WenZhou Science and Technology Bureau (grant no. Y20140092)

Conflict of interest

None

Author contributions

CP designed the study. JH, CX, and BC wrote the manuscript. JH, LJ, and JL performed out the immunohistochemistry and the related statistical analysis. JH, YG, WL, and ZP carried out the cell culture and transfection, Western blot, RT-PCR, and flow cytometry. All authors approved the final version of the manuscript.

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    Affiliations

    1. Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou, Zhejiang Province, China

      Jianjian Hu, Bihuan Cheng & Yuqiang Gong

    2. Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027

      Changlong Xu

    3. Department of Infectious Disease, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, West College Road No.109, Wenzhou City, Zhejiang Province, China, 325027

      Lingxiang Jin, Jie Li, Wei Lin & Chenwei Pan

    4. Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, FuXue lane No.2, Wenzhou, Zhejiang Province, China

      Zhenzhen Pan

    Authors
    1. Jianjian Hu
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    2. Changlong Xu
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    7. Wei Lin
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    Correspondence to Zhenzhen Pan or Chenwei Pan.

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    Jianjian Hu and Changlong Xu contributed equally to this work.

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    Fig. Supplement

    The transfection efficiency of pcDNA3.1-Mcl-1 in HCC cells. (A) HepG2 cells and Huh7 cells were transfected with pcDNA3.1-Mcl-1 plasmid or its control. After 24 h incubation, the Mcl-1 mRNA level was detected by quantitative PCR. (B) Mcl-1 protein level was detected by western blot assay after the HepG2 and Huh7 cells were treated as above. (TIFF 931 kb)

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    Hu, J., Xu, C., Cheng, B. et al. Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy. Tumor Biol. 37, 331–339 (2016). https://doi.org/10.1007/s13277-015-3591-z

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    • DOI: https://doi.org/10.1007/s13277-015-3591-z

    Keywords

    • HCC
    • Imperatorin
    • Cisplatin
    • Mcl-1
    • Apoptosis