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Cytotoxic activity of nemorosone in neuroblastoma cells.

Abstract

Neuroblastoma is the second most common solid tumour during childhood, characterized by rapid disease progression. Most children with metastasized neuroblastoma die despite intensive chemotherapy due to an intrinsic or acquired chemotherapy resistance. Thus, new therapeutic strategies are urgently needed. Here, we demonstrate that the novel compound nemorosone isolated from alcoholic extracts of Clusia rosea resins by reverse phase high pressure liquid chromatography (RP-HPLC) exerts cytotoxic activity in neuroblas-toma cell lines both parental and their clones selected for resistance against adriamycin, cisplatin, etoposide or 5-fluorouracil. Cell cycle studies revealed that nemorosone induces an accumulation in G0/G1- with a reduction in S-phase population combined with a robust up-regulation of p21Cip1. Furthermore, a dose-dependent apoptotic DNA laddering accompanied by an activation of caspase-3 activity was detected. Nemorosone induced a significant dephosphorylation of ERK1/2 in LAN-1 parental cells probably by the inhibition of its upstream kinase MEK1/2. No significant modulation of signal transducers JNK, p38 MAPK and Akt/PKB was detected. The enzymatic activity of immunoprecipitated Akt/PKB was strongly inhibited in vitro, suggesting that nemorosone exerts its anti-proliferative activity at least in part by targeting Akt/PKB in the cell lines studied. In addition, a synergistic effect with Raf-1 inhibitor BAY 43-9006 was found. Finally, nemorosone induced a considerable down-regulation of N-myc protein levels in parental LAN-1 and an etoposide resistant sub-line at the same drug-concentrations.

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  • Authors+Show Affiliations

    ,

    Abteilung Klinische Pharmakologie, Ruhr-Universitaet Bochum, Bochum, Germany. david.diaz-carballo@rub.de

    , , ,

    Source

    MeSH

    Benzophenones
    Caspase 3
    Cell Cycle
    Cell Death
    Cell Line, Tumor
    DNA Damage
    Drug Screening Assays, Antitumor
    Drug Synergism
    Enzyme Activation
    Humans
    Inhibitory Concentration 50
    MAP Kinase Kinase 1
    MAP Kinase Kinase 2
    N-Myc Proto-Oncogene Protein
    Neuroblastoma
    Nuclear Proteins
    Oncogene Proteins
    Phosphorylation
    Protein Kinase Inhibitors
    Proto-Oncogene Proteins c-akt
    Proto-Oncogene Proteins c-raf
    Signal Transduction

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    18194446

    Citation

    Díaz-Carballo, D, et al. "Cytotoxic Activity of Nemorosone in Neuroblastoma Cells." Journal of Cellular and Molecular Medicine, vol. 12, no. 6B, 2008, pp. 2598-608.
    Díaz-Carballo D, Malak S, Bardenheuer W, et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J Cell Mol Med. 2008;12(6B):2598-608.
    Díaz-Carballo, D., Malak, S., Bardenheuer, W., Freistuehler, M., & Reusch, H. P. (2008). Cytotoxic activity of nemorosone in neuroblastoma cells. Journal of Cellular and Molecular Medicine, 12(6B), pp. 2598-608. doi:10.1111/j.1582-4934.2008.00232.x.
    Díaz-Carballo D, et al. Cytotoxic Activity of Nemorosone in Neuroblastoma Cells. J Cell Mol Med. 2008;12(6B):2598-608. PubMed PMID: 18194446.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cytotoxic activity of nemorosone in neuroblastoma cells. AU - Díaz-Carballo,D, AU - Malak,S, AU - Bardenheuer,W, AU - Freistuehler,M, AU - Reusch,H P, PY - 2008/1/16/pubmed PY - 2009/3/26/medline PY - 2008/1/16/entrez SP - 2598 EP - 608 JF - Journal of cellular and molecular medicine JO - J. Cell. Mol. Med. VL - 12 IS - 6B N2 - Neuroblastoma is the second most common solid tumour during childhood, characterized by rapid disease progression. Most children with metastasized neuroblastoma die despite intensive chemotherapy due to an intrinsic or acquired chemotherapy resistance. Thus, new therapeutic strategies are urgently needed. Here, we demonstrate that the novel compound nemorosone isolated from alcoholic extracts of Clusia rosea resins by reverse phase high pressure liquid chromatography (RP-HPLC) exerts cytotoxic activity in neuroblas-toma cell lines both parental and their clones selected for resistance against adriamycin, cisplatin, etoposide or 5-fluorouracil. Cell cycle studies revealed that nemorosone induces an accumulation in G0/G1- with a reduction in S-phase population combined with a robust up-regulation of p21Cip1. Furthermore, a dose-dependent apoptotic DNA laddering accompanied by an activation of caspase-3 activity was detected. Nemorosone induced a significant dephosphorylation of ERK1/2 in LAN-1 parental cells probably by the inhibition of its upstream kinase MEK1/2. No significant modulation of signal transducers JNK, p38 MAPK and Akt/PKB was detected. The enzymatic activity of immunoprecipitated Akt/PKB was strongly inhibited in vitro, suggesting that nemorosone exerts its anti-proliferative activity at least in part by targeting Akt/PKB in the cell lines studied. In addition, a synergistic effect with Raf-1 inhibitor BAY 43-9006 was found. Finally, nemorosone induced a considerable down-regulation of N-myc protein levels in parental LAN-1 and an etoposide resistant sub-line at the same drug-concentrations. SN - 1582-1838 UR - https://www.unboundmedicine.com/medline/citation/18194446/Cytotoxic_activity_of_nemorosone_in_neuroblastoma_cells_ L2 - https://doi.org/10.1111/j.1582-4934.2008.00232.x DB - PRIME DP - Unbound Medicine ER -