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C118P exerted potent anti-tumor effects against melanoma with induction of G2/M arrest via inhibiting the expression of BUB1B

  • Author Footnotes
    1 These authors contributed equally to this work.
    Kun Ren
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Pharmacal Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing, China

    Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Meng Zhou
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Pharmacal Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing, China
    Search for articles by this author
  • Lingjun Li
    Affiliations
    Pharmacal Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing, China
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  • Cheng Wang
    Affiliations
    Department of Dermatology, Zhongda Hospital Southeast Universtiy, Nanjing, PR China
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  • Shengtao Yuan
    Correspondence
    Correspondence to: Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, No. 24 Tong Jia Xiang, Nanjing 210009, PR China.
    Affiliations
    Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
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  • Hongyang Li
    Correspondence
    Correspondence to: Pharmacal Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, 12 jiangwangmiao street, Nanjing 210042, PR China.
    Affiliations
    Pharmacal Research Laboratory, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences, Peking Union Medical College, Nanjing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
Published:November 17, 2022DOI:https://doi.org/10.1016/j.jdermsci.2022.11.003

      Highlights

      • C118P inhibited the proliferation of melanoma cells in a concentration-dependent and time-dependent manner in vitro.
      • C118P simultaneously triggered G2/M arrest and apoptosis via independent mechanisms in melanoma cells.
      • Inhibition of BUB1B significantly enhanced the effects of C118P on G2/M arrest rather than apoptosis.
      • C118P suppressed the tumor growth in A375-xenografted nude mice model via BUB1B inhibition.

      Abstract

      Background

      The incidence of melanoma rapidly increased in the past decades, and the clinical treatment of melanoma met huge challenges because of tumor heterogeneity and drug resistance. C118P, a novel tubulin polymerization inhibitor, exhibited strong anticancer effects in many tumors. However, there was no data regarding the potential effects of C118P in melanoma cells.

      Objective

      To investigate of the efficacy and potential target of C118P in melanoma cells.

      Methods

      Human melanoma cells were treated with C118P, followed by assessments of proliferation, apoptosis and cell cycle distribution. Subsequently, RNA sequencing was performed to further identify the drug targets of C118P in melanoma cells. GO analysis and protein-protein interaction networks analysis were used to screen the potential targets, and verified by a series of assays. Finally, the anti-growth activity of C118P was evaluated in A375-xenografted nude mice, and the expression of BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B), Ki67 and Tunel were determined.

      Results

      We found that C118P concentration-dependently inhibited proliferation of melanoma cells. Moreover, C118P simultaneously triggered dramatic G2/M arrest and apoptosis via independent mechanisms in melanoma cells in vitro. C118P exerted anti-melanoma effects by inducing potent G2/M arrest, which was mechanistically related to downregulation of the expression of BUB1B. Importantly, C118P inhibited the tumor growth in A375-xenografted nude, and increased the staining of Ki-67 and Tunel and suppressed the expression of BUB1B in melanoma tissues, which was consistent with in vitro study.

      Conclusion

      C118P might provide a novel strategy for the clinical treatment of melanoma by inhibition of BUB1B.

      Keywords

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