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      Brusatol-mediated induction of leukemic cell differentiation and G(1) arrest is associated with down-regulation of c-myc.

      Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
      Brucea, Cell Differentiation, drug effects, DNA Primers, chemistry, Down-Regulation, Flow Cytometry, G1 Phase, Gene Expression Regulation, Leukemic, Humans, Immunophenotyping, Leukemia, Myeloid, metabolism, pathology, Lymphocytes, Phytotherapy, Plant Preparations, Proto-Oncogene Proteins c-myc, genetics, Quassins, pharmacology, RNA, Messenger, analysis, RNA, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured

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          Abstract

          Employing the natural product quassinoid brusatol, we currently report cellular and molecular events leading to cell death or terminal differentiation in a panel of leukemic cells. Brusatol and bruceantin exerted significant cytotoxic effects with several leukemic cell lines, but not with K562 or normal lymphocytic cells. Cell lines that were less sensitive to the cytotoxic effects of brusatol responded primarily through induction of terminal differentiation. The differentiated phenotype in cell lines derived from acute or chronic myeloid leukemias (HL-60, K562, Kasumi-1, NB4, U937, BV173) was characterized for producing superoxide and non-specific esterase, and some with up-regulation of CD13 (cluster of differentiation) and down-regulation of CD15. Chronic myeloid leukemic cell lines, K562 and BV173, and acute lymphoblastic cell lines, SUPB13 and RS4;11, were induced to differentiate along the erythrocytic pathway. Withdrawal studies showed that brusatol treatment for 48 h was sufficient to induce commitment towards terminal differentiation in HL-60, K562 and SUPB13. Reh cells did not undergo maturation. Analysis of c-MYC protein expression revealed that brusatol or bruceantin down-regulated expression to undetectable levels in cell lines that were most sensitive, based on cell death or terminal differentiation. Generally, c-myc RNA was reduced, but to a lower extent than c-MYC protein levels, indicating c-myc expression was regulated by quassinoids at the post-transcriptional level. Thus, regulation of c-myc expression may represent a critical event that leads to terminal differentiation. Since these responses are facilitated at clinically achievable concentrations, quassinoids may be of value for the management of hematological malignancies.

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