التفاصيل البيبلوغرافية
| العنوان: |
The Therapeutic Efficacy and Mechanism of Action of Gnetin C, a Natural Compound from the Melinjo Plant, in a Preclinical Mouse Model of Advanced Prostate Cancer. |
| المؤلفون: |
Campanelli, Gisella, Francois, Ekniel, Parupathi, Prashanth, Devarakonda, Lakshmi Sirisha, Yang, Ching, Kumar, Avinash, Levenson, Anait S. |
| المصدر: |
Cancers; Apr2024, Vol. 16 Issue 7, p1344, 15p |
| مصطلحات موضوعية: |
PHYTOTHERAPY, BIOLOGICAL models, PROTEINS, PROSTATE-specific antigen, RESEARCH funding, CELL proliferation, APOPTOSIS, PROSTATE tumors, CELLULAR signal transduction, DESCRIPTIVE statistics, PLANT extracts, MICE, MEDICINAL plants, DRUG efficacy, ANIMAL experimentation, MOLECULAR structure, MTOR inhibitors, POLYPHENOLS, EVALUATION |
| مستخلص: |
Simple Summary: Incidence and mortality rates for prostate cancer remain high due to advanced disease characterized by the heterogeneous activation of numerous molecular pathways. In the current study, utilizing a genetic mouse model of advanced prostate cancer with hyperactivated metastasis-associated protein 1/mammalian target of rapamycin (MTA1/mTOR) tumor-promoting pathway, we show for the first time that gnetin C, a natural compound from the melinjo plant, blocks the progression of prostate cancer by reducing cell proliferation and angiogenesis and promoting cell death through the efficient targeting of the MTA1/mTOR pathway. These data may provide a foundation from which to explore gnetin C as a monotherapy and/or combination therapy with approved drugs against advanced prostate cancer in patients with a loss of phosphatase and tensin homolog (PTEN) expression and activated MTA1/mTOR signaling. The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26MTA1; Ptenf/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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