7-epi-nemorosone from Clusia rosea induces apoptosis, androgen receptor down-regulation and dysregulation of PSA levels in LNCaP prostate carcinoma cells
| Autor: | Holger Jastrow, Walter Bardenheuer, Süleyman Ergün, Helmut Buehler, Dirk Strumberg, Ali Haydar Acikelli, Sebastian Gustmann, David Diaz-Carballo |
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| Rok vydání: | 2012 |
| Předmět: |
Male
MAPK/ERK pathway medicine.medical_specialty Medizin Down-Regulation Pharmaceutical Science Apoptosis Propolis Benzophenones Prostate cancer Cyclin-dependent kinase Cell Line Tumor Cyclins Internal medicine Drug Discovery LNCaP medicine Animals Humans Phosphorylation Clusia Protein kinase B Pharmacology biology Plant Extracts Kinase Carcinoma Cell Cycle Prostate Prostatic Neoplasms Bees Prostate-Specific Antigen medicine.disease Antineoplastic Agents Phytogenic Drug Resistance Multiple Androgen receptor Endocrinology Complementary and alternative medicine MCF-7 Receptors Androgen Androgens Cancer research biology.protein Molecular Medicine Kallikreins Mitogen-Activated Protein Kinases Proto-Oncogene Proteins c-akt Phytotherapy Signal Transduction |
| Zdroj: | Phytomedicine. 19:1298-1306 |
| ISSN: | 0944-7113 |
| DOI: | 10.1016/j.phymed.2012.08.004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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