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AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

Gang Shen, Jianchun Chen, Yongqiang Zhou

    Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
    |October 12, 2018
    PubMed
    Abstract

    Insights

    The novel bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 effectively reduced prostate cancer cell proliferation and survival. Combination therapy with an AKT inhibitor enhanced AZD5153

    Area of Science:

    • Oncology
    • Molecular Biology
    • Pharmacology

    Background:

    • Bromodomain-containing protein 4 (BRD4) overexpression drives prostate cancer progression by upregulating oncogenes.
    • AZD5153 is a novel inhibitor targeting BRD4.

    Purpose of the Study:

    • To evaluate the therapeutic potential of AZD5153 in prostate cancer.
    • To investigate the mechanisms underlying AZD5153's efficacy and resistance.

    Main Methods:

    • In vitro studies utilized prostate cancer cell lines treated with AZD5153, assessing survival, proliferation, apoptosis, cell cycle, and signaling pathways.
    • In vivo efficacy was tested using a PC-3 xenograft model in nude mice.
    • AKT's role as a resistance factor was investigated through inhibition and depletion studies.

    Main Results:

    • AZD5153 inhibited prostate cancer cell proliferation and survival, inducing apoptosis and cell cycle arrest.
    • The drug downregulated key BRD4 targets, including cyclin D1, Myc, Bcl-2, FOSL1, and CDK4.
    • AKT was identified as a resistance factor; its inhibition sensitized cells to AZD5153 and enhanced anti-tumor activity in vivo when combined with MK-2206.

    Conclusions:

    • AZD5153 demonstrates significant anti-prostate cancer activity by targeting BRD4.
    • Combining AZD5153 with AKT inhibitors like MK-2206 may represent a potent therapeutic strategy for prostate cancer.
    Keywords:
    AKTAZD5153BRD4ChemosensitizationProstate cancer

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