Abstract
Bone metastasis is a major cause of prostate cancer (PCa) mortality. Although docetaxel chemotherapy initially extends patients' survival, in most cases PCa becomes chemoresistant and eventually progresses without a cure. In this study, we developed a novel small-molecule compound BKM1972, which exhibited potent in vitro cytotoxicity in PCa and other cancer cells regardless of their differences in chemo-responsiveness. Mechanistic studies demonstrated that BKM1972 effectively inhibited the expression of anti-apoptotic protein survivin and membrane-bound efflux pump ATP binding cassette B 1 (ABCB1, p-glycoprotein), presumably via signal transducer and activator of transcription 3 (Stat3). BKM1972 was well tolerated in mice and as a monotherapy, significantly inhibited the intraosseous growth of chemosensitive and chemoresistant PCa cells. These results indicate that BKM1972 is a promising small-molecule lead to treat PCa bone metastasis and overcome docetaxel resistance.
Keywords:
Bone metastasis; Chemoresistance; Preclinical model; Prostate cancer; Small-molecule therapy.
Copyright © 2019 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Bone Neoplasms / drug therapy*
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Bone Neoplasms / genetics
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Bone Neoplasms / metabolism
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Bone Neoplasms / secondary
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Bradykinin Receptor Antagonists / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Docetaxel / pharmacology*
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Drug Resistance, Neoplasm*
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Humans
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Male
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Mice, Nude
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Molecular Targeted Therapy
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Organophosphonates / pharmacology*
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Phosphorylation
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Survivin / genetics
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Survivin / metabolism
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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Antineoplastic Agents
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BIRC5 protein, human
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Bradykinin Receptor Antagonists
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Organophosphonates
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STAT3 Transcription Factor
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STAT3 protein, human
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Survivin
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Docetaxel