A cisplatin derivative that inhibits collagen fibril-formation in vitro

Miyu Zenda, Hiroyuki Yasui, Shinya Oishi, Ryo Masuda, Nobutaka Fujii, Takaki Koide

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    Abstract

    Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt(NH<inf>3</inf>)<inf>2</inf>(Cl)(DMSO)]<sup>+</sup>. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. cis-Diamminedichloroplatinum(II) (cisplatin) dissolved in dimethylsulfoxide (DMSO) was discovered as a potential inhibitor of collagen fibril-formation. This platinum complex exhibited inhibitory effects on in vitro collagen fibril-formation and in situ collagen-deposition in a cell culture system, whereas its cytotoxicity was hardly observed. The active species was suggested to be [Pt(NH<inf>3</inf>)<inf>2</inf>(Cl)(DMSO)]<sup>+</sup>, which targeted His and/or Met residues on the collagen triple-helix.

    Original languageEnglish
    Pages (from-to)519-526
    Number of pages8
    JournalChemical Biology and Drug Design
    Volume85
    Issue number5
    DOIs
    Publication statusPublished - 2015 May 1

    Fingerprint

    Cisplatin
    Dimethyl Sulfoxide
    Collagen
    Derivatives
    Platinum
    Cytotoxicity
    Cell culture
    Cell Culture Techniques
    In Vitro Techniques
    Molecules
    Endothelial cells
    Human Umbilical Vein Endothelial Cells
    Structure-Activity Relationship
    Antineoplastic Agents
    Self assembly
    Mass spectrometry
    Conformations
    Mass Spectrometry
    Screening
    Binding Sites

    Keywords

    • cisplatin
    • collagen
    • dimethylsulphoxide
    • fibril-formation
    • peptide

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine

    Cite this

    A cisplatin derivative that inhibits collagen fibril-formation in vitro. / Zenda, Miyu; Yasui, Hiroyuki; Oishi, Shinya; Masuda, Ryo; Fujii, Nobutaka; Koide, Takaki.

    In: Chemical Biology and Drug Design, Vol. 85, No. 5, 01.05.2015, p. 519-526.

    Research output: Contribution to journalArticle

    Zenda, Miyu ; Yasui, Hiroyuki ; Oishi, Shinya ; Masuda, Ryo ; Fujii, Nobutaka ; Koide, Takaki. / A cisplatin derivative that inhibits collagen fibril-formation in vitro. In: Chemical Biology and Drug Design. 2015 ; Vol. 85, No. 5. pp. 519-526.
    @article{3fe4e0c391444cbda4b286e884b83888,
    title = "A cisplatin derivative that inhibits collagen fibril-formation in vitro",
    abstract = "Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt(NH3)2(Cl)(DMSO)]+. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. cis-Diamminedichloroplatinum(II) (cisplatin) dissolved in dimethylsulfoxide (DMSO) was discovered as a potential inhibitor of collagen fibril-formation. This platinum complex exhibited inhibitory effects on in vitro collagen fibril-formation and in situ collagen-deposition in a cell culture system, whereas its cytotoxicity was hardly observed. The active species was suggested to be [Pt(NH3)2(Cl)(DMSO)]+, which targeted His and/or Met residues on the collagen triple-helix.",
    keywords = "cisplatin, collagen, dimethylsulphoxide, fibril-formation, peptide",
    author = "Miyu Zenda and Hiroyuki Yasui and Shinya Oishi and Ryo Masuda and Nobutaka Fujii and Takaki Koide",
    year = "2015",
    month = "5",
    day = "1",
    doi = "10.1111/cbdd.12450",
    language = "English",
    volume = "85",
    pages = "519--526",
    journal = "Chemical Biology and Drug Design",
    issn = "1747-0277",
    publisher = "Blackwell",
    number = "5",

    }

    TY - JOUR

    T1 - A cisplatin derivative that inhibits collagen fibril-formation in vitro

    AU - Zenda, Miyu

    AU - Yasui, Hiroyuki

    AU - Oishi, Shinya

    AU - Masuda, Ryo

    AU - Fujii, Nobutaka

    AU - Koide, Takaki

    PY - 2015/5/1

    Y1 - 2015/5/1

    N2 - Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt(NH3)2(Cl)(DMSO)]+. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. cis-Diamminedichloroplatinum(II) (cisplatin) dissolved in dimethylsulfoxide (DMSO) was discovered as a potential inhibitor of collagen fibril-formation. This platinum complex exhibited inhibitory effects on in vitro collagen fibril-formation and in situ collagen-deposition in a cell culture system, whereas its cytotoxicity was hardly observed. The active species was suggested to be [Pt(NH3)2(Cl)(DMSO)]+, which targeted His and/or Met residues on the collagen triple-helix.

    AB - Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum(II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide (DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt(NH3)2(Cl)(DMSO)]+. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. cis-Diamminedichloroplatinum(II) (cisplatin) dissolved in dimethylsulfoxide (DMSO) was discovered as a potential inhibitor of collagen fibril-formation. This platinum complex exhibited inhibitory effects on in vitro collagen fibril-formation and in situ collagen-deposition in a cell culture system, whereas its cytotoxicity was hardly observed. The active species was suggested to be [Pt(NH3)2(Cl)(DMSO)]+, which targeted His and/or Met residues on the collagen triple-helix.

    KW - cisplatin

    KW - collagen

    KW - dimethylsulphoxide

    KW - fibril-formation

    KW - peptide

    UR - http://www.scopus.com/inward/record.url?scp=84927136694&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84927136694&partnerID=8YFLogxK

    U2 - 10.1111/cbdd.12450

    DO - 10.1111/cbdd.12450

    M3 - Article

    VL - 85

    SP - 519

    EP - 526

    JO - Chemical Biology and Drug Design

    JF - Chemical Biology and Drug Design

    SN - 1747-0277

    IS - 5

    ER -