{
    "abstract": "Cardiac glycosides (CGs) have been used for decades to treat heart failure and arrhythmic diseases. Recent non-clinical and epidemiological findings have suggested that CGs exhibit anti-tumor activities. Therefore, CGs may be repositioned as drugs for the treatment of cancer. A detailed understanding of the anti-cancer mechanisms of CGs is essential for their application to the treatment of targetable cancer types. To elucidate the factors associated with the anti-tumor effects of CGs, we performed transcriptome profiling on human multiple myeloma AMO1 cells treated with periplocin, one of the CGs. Periplocin significantly down-regulated the transcription of MYC (c-Myc), a well-established oncogene. Periplocin also suppressed c-Myc expression at the protein levels. This repression of c-Myc was also observed in several cell lines. To identify target proteins for the inhibition of c-Myc, we generated CG-resistant (C9) cells using a sustained treatment with digoxin. We confirmed that C9 cells acquired resistance to the inhibition of c-Myc expression and cell proliferation by CGs. Moreover, the sequencing of genomic DNA in C9 cells revealed the mutation of D128N in \u03b11-Na/K-ATPase, indicating the target protein. These results suggest that CGs suppress c-Myc expression in cancer cells via \u03b11-Na/K-ATPase, which provides further support for the anti-tumor activities of CGs.",
    "authors": [
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Muneshige",
            "initials": "M",
            "lastname": "Tokugawa"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Yasumichi",
            "initials": "Y",
            "lastname": "Inoue"
        },
        {
            "affiliation": "Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Hiromasa",
            "initials": "H",
            "lastname": "Aoki"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Chiharu",
            "initials": "C",
            "lastname": "Miyajima"
        },
        {
            "affiliation": "Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Kan'ichiro",
            "initials": "K",
            "lastname": "Ishiuchi"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Kento",
            "initials": "K",
            "lastname": "Tsurumi"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Chisane",
            "initials": "C",
            "lastname": "Kujirai"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.\nChordia Therapeutics Inc., 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan.",
            "firstname": "Daisuke",
            "initials": "D",
            "lastname": "Morishita"
        },
        {
            "affiliation": "Plant research section, The Kochi Prefectural Makino Botanical Garden, 4200-6 Godaiyama, Kochi 781-8125, Japan.",
            "firstname": "Michiyo",
            "initials": "M",
            "lastname": "Matsuno"
        },
        {
            "affiliation": "Plant research section, The Kochi Prefectural Makino Botanical Garden, 4200-6 Godaiyama, Kochi 781-8125, Japan.",
            "firstname": "Hajime",
            "initials": "H",
            "lastname": "Mizukami"
        },
        {
            "affiliation": "Department of Hematology and Oncology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.",
            "firstname": "Masaki",
            "initials": "M",
            "lastname": "Ri"
        },
        {
            "affiliation": "Department of Hematology and Oncology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.",
            "firstname": "Shinsuke",
            "initials": "S",
            "lastname": "Iida"
        },
        {
            "affiliation": "Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Toshiaki",
            "initials": "T",
            "lastname": "Makino"
        },
        {
            "affiliation": "Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Mineyoshi",
            "initials": "M",
            "lastname": "Aoyama"
        },
        {
            "affiliation": "Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.",
            "firstname": "Hidetoshi",
            "initials": "H",
            "lastname": "Hayashi"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.",
    "doi": "10.1093/jb/mvad085",
    "journal": "Journal of biochemistry",
    "keywords": [
        "c-Myc",
        "cardiac glycosides",
        "multiple myeloma",
        "periplocin",
        "\u03b11-Na/K-ATPase.Abbreviations: \u03b11-NKA, \u03b11-Na/K-ATPase; CG, cardiac glycoside"
    ],
    "methods": null,
    "publication_date": "2023-11-10",
    "pubmed_id": "37948630",
    "results": null,
    "title": "Involvement of cardiac glycosides targeting Na/K-ATPase in their inhibitory effects on c-Myc expression via its transcription, translation and proteasomal degradation.",
    "xml": "<Element 'PubmedArticle' at 0x78850328d170>"
}