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Molecular Pharmacology

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Research ArticleArticle

Caspase Activation in MCF7 Cells Responding to Etoposide Treatment

Christopher W. Benjamin, Ronald R. Hiebsch and David A. Jones
Molecular Pharmacology March 1998, 53 (3) 446-450; DOI: https://doi.org/10.1124/mol.53.3.446
Christopher W. Benjamin
Department of Cardiovascular Pharmacology, Pharmacia and Upjohn Company, Kalamazoo, Michigan 49001
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Ronald R. Hiebsch
Department of Cardiovascular Pharmacology, Pharmacia and Upjohn Company, Kalamazoo, Michigan 49001
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David A. Jones
Department of Cardiovascular Pharmacology, Pharmacia and Upjohn Company, Kalamazoo, Michigan 49001
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Abstract

Studies of the biochemical mechanisms evoked by conventional treatments for neoplastic diseases point to apoptosis as a key process for elimination of unwanted cells. Although the pathways through which chemotherapeutics promote cell death remain largely unknown, caspase proteases play a central role in the induction of apoptosis in response to a variety of stimuli including tumor necrosis factor, fas ligand, and growth factor deprivation. In this article, we demonstrate the induction of caspase protease activity in MCF7 human breast carcinoma cells exposed to the topoisomerase inhibitor, etoposide. Caspase protease activity was assessed by incubating cell lysates with the known caspase substrates, acetyl-l-aspartic-l-glutamic-l-valyl-l-aspartic acid 4-methyl-7-aminocoumarin or acetyl-l-tyrosyl-l-valyl-l-aspartic acid 4-methyl-7-aminocoumarin. We observed maximal cleavage of acetyl-l-aspartic-l-glutamic-l-valyl-l-aspartic acid 4-methyl-7-aminocoumarin within 6 hr following etoposide addition, a time that precedes cell death. In contrast, acetyl-l-tyrosyl-l-valyl-l-aspartic acid 4-methyl-7-aminocoumarin was resistant to cleavage activity. This substrate cleavage specificity implies that a caspase-3-like protease is activated in response to DNA damage. Consistent with the lysate protease activity, an intracellular marker of caspase activation, poly-ADP ribose polymerase (PARP), was cleaved in a concentration- and time-dependent manner after etoposide-treatment. PARP cleavage followed caspase activation and reached maximum cleavage between 12 and 16 hr. Incubation of the cells with the peptidic caspase inhibitor z-valine-alanine-asparagine-CH2F prevented caspase activation, inhibited PARP cleavage, and inhibited cell death. Thus, etoposide killing of MCF7 cells requires a caspase-3-like protease.

Footnotes

    • Received August 26, 1997.
    • Accepted December 3, 1997.
  • Send reprint requests to: Dr. Christopher W. Benjamin, Senior Research Biochemist, Department of Cardiovascular Pharmacology, Pharmacia and Upjohn Company, 301 Henrietta Street, Kalamazoo, MI 49001. E-mail: cwbenjam{at}am.pnu.com

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Molecular Pharmacology: 53 (3)
Molecular Pharmacology
Vol. 53, Issue 3
1 Mar 1998
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Research ArticleArticle

Caspase Activation in MCF7 Cells Responding to Etoposide Treatment

Christopher W. Benjamin, Ronald R. Hiebsch and David A. Jones
Molecular Pharmacology March 1, 1998, 53 (3) 446-450; DOI: https://doi.org/10.1124/mol.53.3.446

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Research ArticleArticle

Caspase Activation in MCF7 Cells Responding to Etoposide Treatment

Christopher W. Benjamin, Ronald R. Hiebsch and David A. Jones
Molecular Pharmacology March 1, 1998, 53 (3) 446-450; DOI: https://doi.org/10.1124/mol.53.3.446
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