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Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells.

Abstract

Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24-72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy.

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  • Authors+Show Affiliations

    ,

    Department of Dermatology, University of Alabama at Birmingham, Volker Hall 557, 1670 University Boulevard, P.O. Box 202, Birmingham, AL 35294, USA.

    ,

    Source

    Molecular cancer therapeutics 5:2 2006 Feb pg 296-308

    MeSH

    Androgens
    Antineoplastic Agents, Phytogenic
    Apoptosis
    Berberine
    Carcinoma
    Caspase 3
    Caspase Inhibitors
    Caspases
    Cell Cycle
    Cell Cycle Proteins
    Cell Line, Tumor
    Cell Proliferation
    Cytochromes c
    Enzyme Activation
    Epithelial Cells
    G1 Phase
    Humans
    Male
    Membrane Potentials
    Mitochondria
    Poly(ADP-ribose) Polymerases
    Prostatic Neoplasms
    Proto-Oncogene Proteins c-bcl-2

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    16505103

    Citation

    Mantena, Sudheer K., et al. "Berberine, a Natural Product, Induces G1-phase Cell Cycle Arrest and Caspase-3-dependent Apoptosis in Human Prostate Carcinoma Cells." Molecular Cancer Therapeutics, vol. 5, no. 2, 2006, pp. 296-308.
    Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther. 2006;5(2):296-308.
    Mantena, S. K., Sharma, S. D., & Katiyar, S. K. (2006). Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Molecular Cancer Therapeutics, 5(2), pp. 296-308.
    Mantena SK, Sharma SD, Katiyar SK. Berberine, a Natural Product, Induces G1-phase Cell Cycle Arrest and Caspase-3-dependent Apoptosis in Human Prostate Carcinoma Cells. Mol Cancer Ther. 2006;5(2):296-308. PubMed PMID: 16505103.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. AU - Mantena,Sudheer K, AU - Sharma,Som D, AU - Katiyar,Santosh K, PY - 2006/3/1/pubmed PY - 2006/5/5/medline PY - 2006/3/1/entrez SP - 296 EP - 308 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 5 IS - 2 N2 - Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24-72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy. SN - 1535-7163 UR - https://www.unboundmedicine.com/medline/citation/16505103/Berberine_a_natural_product_induces_G1_phase_cell_cycle_arrest_and_caspase_3_dependent_apoptosis_in_human_prostate_carcinoma_cells_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=16505103 DB - PRIME DP - Unbound Medicine ER -