Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341

DOI PDF 被引用文献9件
  • Teru Hideshima
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Constantine Mitsiades
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Masaharu Akiyama
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Toshiaki Hayashi
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Dharminder Chauhan
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Paul Richardson
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Robert Schlossman
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Klaus Podar
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Nikhil C. Munshi
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Nicholas Mitsiades
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
  • Kenneth C. Anderson
    From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

抄録

<jats:p>We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341–induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.</jats:p>

収録刊行物

  • Blood

    Blood 101 (4), 1530-1534, 2003-02-15

    American Society of Hematology

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