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Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib

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Abstract

Purpose

MBRI-001 is a novel synthetic derivative of plinabulin. In this study, our purpose is to investigate the inhibition effects of MBRI-001 on human hepatocellular carcinoma as monotherapy or in combination with sorafenib.

Methods

HCCLM3 and Bel-7402 cell lines were used for activity evaluation in vitro. The anti-proliferative activity of MBRI-001 was assessed by MTT assay. The morphological change of microtubules was determined by immunofluorescence assay. The cell cycle was measured by flow cytometer. The expression of cyclin B1 (CCNB1) was analyzed by RT-qPCR and western blotting assays. The antitumor activities in vivo were evaluated with human HCC xenograft mice model.

Results

Our data demonstrated that MBRI-001 had better anti-proliferative activities than that of plinabulin against HCCLM3 and Bel-7402 cell lines. MBRI-001 inhibited the formation of microtubules and induced G2/M arrest with the downregulation of CCNB1. In vivo orthotopic mice model demonstrated that MBRI-001 significantly inhibited the growth of HCCLM3 with the apoptosis and necrosis observed in tumor. The combination treatment of MBRI-001 with sorafenib in subcutaneous mice model exhibited a higher antitumor inhibition rate at 72.0%, in comparison with MBRI-001 or sorafenib as monotherapy at 40.7% or 47.7%, respectively.

Conclusion

MBRI-001 had better inhibition effects on microtubules and human hepatocellular carcinoma than that of plinabulin. The combination treatment of MBRI-001 and sorafenib exhibited a higher antitumor effect, which could provide a new strategy to treat HCC in the future.

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Funding

This study was funded by “Zhufeng Scholar Program” of Ocean University of China (841412016), “Major Projects of Independent Innovation” of Qingdao (15-4-13-zdzx-hy), “Outstanding Talents Plan” of Qingdao (15-10-3-15-(34)-zch), Aoshan Talents Cultivation Program of Qingdao National Laboratory for Marine Science and Technology (No.2017ASTCP-OS08) to Dr. Wenbao Li, National Natural Science Foundation of China (NSFC 81472687 and 81773761) to Dr. Linna Li, and youth special fund for PhD of Qingdao (No.16-5-1-62-jch) to Dr. Jianchun Zhao.

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Authors and Affiliations

  1. School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China

    Mengyan Deng, Jianchun Zhao & Wenbao Li

  2. Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China

    Wenbao Li

  3. Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, 100850, China

    Linna Li & Shoujun Yuan

  4. Marine Biomedical Research Institute of Qingdao, Qingdao, 266071, China

    Jianchun Zhao & Wenbao Li

Authors
  1. Mengyan Deng
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  2. Linna Li
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Corresponding authors

Correspondence to Shoujun Yuan or Wenbao Li.

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All authors declare that there is no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Deng, M., Li, L., Zhao, J. et al. Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib. Cancer Chemother Pharmacol 81, 853–862 (2018). https://doi.org/10.1007/s00280-018-3547-2

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  • DOI: https://doi.org/10.1007/s00280-018-3547-2

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