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Research ArticleArticle

The Novel Triterpenoid CDDO Induces Apoptosis and Differentiation of Human Osteosarcoma Cells by a Caspase-8 Dependent Mechanism

Yasumasa Ito, Pramod Pandey, Michael B. Sporn, Rakesh Datta, Surender Kharbanda and Donald Kufe
Molecular Pharmacology May 2001, 59 (5) 1094-1099; DOI: https://doi.org/10.1124/mol.59.5.1094
Yasumasa Ito
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Pramod Pandey
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Michael B. Sporn
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Rakesh Datta
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Surender Kharbanda
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Donald Kufe
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (Y.I., P.P., R.D., S.K., D.K.), and 2Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire (M.B.S.)
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Abstract

The oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multifunctional molecule that induces monocytic differentiation of human myeloid leukemia cells and inhibits proliferation of diverse human tumor cell lines. The present studies on human osteosarcoma cells demonstrate that CDDO induces mitochondrial cytochrome crelease, caspase-3 activation, and internucleosomal DNA fragmentation. Overexpression of the caspase-8 inhibitor CrmA blocked CDDO-induced cytochrome c release and apoptosis. By contrast, overexpression of the antiapoptotic Bcl-xL protein blocked CDDO-induced cytochrome c release, but only partly inhibited caspase-3 activation and apoptosis. In concert with these findings, we demonstrate that CDDO: 1) activates caspase-8 and thereby caspase-3 by a cytochrome c-independent mechanism and 2) induces cytochrome c release by caspase-8-dependent cleavage of Bid. The results also demonstrate that treatment of osteosarcoma cells with CDDO induces differentiation, as assessed by alkaline phosphatase activity and osteocalcin production, and that this response is abrogated in cells that overexpress CrmA. These findings demonstrate that CDDO induces both osteoblastic differentiation and apoptosis by caspase-8-dependent mechanisms.

Footnotes

    • Received November 6, 2000.
    • Accepted January 22, 2001.
  • Send reprint requests to: Dr. Donald W. Kufe, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail: donald_kufe{at}dfci.harvard.edu

  • This investigation was supported by National Cancer Institute Grant CA42802.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (5)
Molecular Pharmacology
Vol. 59, Issue 5
1 May 2001
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Research ArticleArticle

The Novel Triterpenoid CDDO Induces Apoptosis and Differentiation of Human Osteosarcoma Cells by a Caspase-8 Dependent Mechanism

Yasumasa Ito, Pramod Pandey, Michael B. Sporn, Rakesh Datta, Surender Kharbanda and Donald Kufe
Molecular Pharmacology May 1, 2001, 59 (5) 1094-1099; DOI: https://doi.org/10.1124/mol.59.5.1094

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Research ArticleArticle

The Novel Triterpenoid CDDO Induces Apoptosis and Differentiation of Human Osteosarcoma Cells by a Caspase-8 Dependent Mechanism

Yasumasa Ito, Pramod Pandey, Michael B. Sporn, Rakesh Datta, Surender Kharbanda and Donald Kufe
Molecular Pharmacology May 1, 2001, 59 (5) 1094-1099; DOI: https://doi.org/10.1124/mol.59.5.1094
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