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7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells.

Abstract

The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines. Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. In spite of the current therapeutic options for this cancer entity, many patients die due to metastases in distant organs and acquired chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora (Clusiaceae), has been described to be a potent antitumoral agent. Here, its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1(+) sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot. Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug. ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer.

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  • Authors+Show Affiliations

    ,

    Ruhr University of Bochum, Marienhospital Herne, Herne, Germany.

    , , , , , ,

    Source

    MeSH

    Androgens
    Animals
    Antineoplastic Agents, Phytogenic
    Apoptosis
    Bees
    Benzophenones
    Carcinoma
    Cell Cycle
    Cell Line, Tumor
    Clusia
    Cyclins
    Down-Regulation
    Drug Resistance, Multiple
    Humans
    Kallikreins
    Male
    Mitogen-Activated Protein Kinases
    Phosphorylation
    Phytotherapy
    Plant Extracts
    Propolis
    Prostate
    Prostate-Specific Antigen
    Prostatic Neoplasms
    Proto-Oncogene Proteins c-akt
    Receptors, Androgen
    Signal Transduction

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22981203

    Citation

    Díaz-Carballo, David, et al. "7-epi-nemorosone From Clusia Rosea Induces Apoptosis, Androgen Receptor Down-regulation and Dysregulation of PSA Levels in LNCaP Prostate Carcinoma Cells." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 19, no. 14, 2012, pp. 1298-306.
    Díaz-Carballo D, Gustmann S, Acikelli AH, et al. 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. Phytomedicine. 2012;19(14):1298-306.
    Díaz-Carballo, D., Gustmann, S., Acikelli, A. H., Bardenheuer, W., Buehler, H., Jastrow, H., ... Strumberg, D. (2012). 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 19(14), pp. 1298-306. doi:10.1016/j.phymed.2012.08.004.
    Díaz-Carballo D, et al. 7-epi-nemorosone From Clusia Rosea Induces Apoptosis, Androgen Receptor Down-regulation and Dysregulation of PSA Levels in LNCaP Prostate Carcinoma Cells. Phytomedicine. 2012 Nov 15;19(14):1298-306. PubMed PMID: 22981203.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells. AU - Díaz-Carballo,David, AU - Gustmann,Sebastian, AU - Acikelli,Ali Haydar, AU - Bardenheuer,Walter, AU - Buehler,Helmut, AU - Jastrow,Holger, AU - Ergun,Suleyman, AU - Strumberg,Dirk, Y1 - 2012/09/14/ PY - 2012/03/30/received PY - 2012/06/30/revised PY - 2012/08/05/accepted PY - 2012/9/18/entrez PY - 2012/9/18/pubmed PY - 2013/4/27/medline SP - 1298 EP - 306 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 19 IS - 14 N2 - The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines. Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. In spite of the current therapeutic options for this cancer entity, many patients die due to metastases in distant organs and acquired chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora (Clusiaceae), has been described to be a potent antitumoral agent. Here, its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1(+) sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot. Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug. ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/22981203/7_epi_nemorosone_from_Clusia_rosea_induces_apoptosis_androgen_receptor_down_regulation_and_dysregulation_of_PSA_levels_in_LNCaP_prostate_carcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(12)00253-X DB - PRIME DP - Unbound Medicine ER -