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Molecular Pharmacology

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Research ArticleArticle

Dithiothreitol Enhances Arsenic Trioxide-Induced Apoptosis in NB4 Cells

Jia-Ran Gurr, Da-Tian Bau, Fount Liu, Shugene Lynn and Kun-Yan Jan
Molecular Pharmacology July 1999, 56 (1) 102-109; DOI: https://doi.org/10.1124/mol.56.1.102
Jia-Ran Gurr
Institute of Zoology, Academia Sinica, Taipei, Republic of China
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Da-Tian Bau
Institute of Zoology, Academia Sinica, Taipei, Republic of China
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Fount Liu
Institute of Zoology, Academia Sinica, Taipei, Republic of China
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Shugene Lynn
Institute of Zoology, Academia Sinica, Taipei, Republic of China
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Kun-Yan Jan
Institute of Zoology, Academia Sinica, Taipei, Republic of China
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Abstract

Recently, arsenic trioxide (As2O3) was reported to induce clinical remission in patients with acute promyelocytic leukemia. Modulation of protein phosphorylation by binding to the vicinal thiols has been suggested as a possible mechanism. We found that phenylarsine oxide, a strong vicinal thiol-binding agent, neither induced nuclear fragmentation or DNA laddering nor increased caspase activity in NB4 cells; however, As2O3 and a weak thiol-binding agent, dimethylarsinic acid, did increase activity. Dithiothreitol (DTT) effectively suppressed the phenylarsine oxide-inhibited cellular reductive capacity, but unexpectedly, enhanced As2O3-induced apoptosis in NB4 cells. As2O3-induced and As2O3-plus-DTT-induced apoptosis in NB4 cells was modulated by oxidant modifiers, but not by nitric oxide synthase inhibitors. These results demonstrate that DTT, a dithiol agent and known antidote for trivalent inorganic arsenic, enhances the toxicity of As2O3, thereby opening a new research direction for the mechanisms of arsenic toxicity and perhaps also helping in the development of new therapeutic strategies for treating leukemias.

Footnotes

    • Received November 24, 1998.
    • Accepted March 29, 1999.
  • Send reprint requests to: Dr. K. Y. Jan, Institute of Zoology, Academia Sinica, Taipei 11529, ROC. E-mail:zojky{at}sinica.edu.tw

  • Supported by grants from Academia Sinica and National Sciences Council (NSC87–2312-B001–008), Republic of China.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (1)
Molecular Pharmacology
Vol. 56, Issue 1
1 Jul 1999
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Research ArticleArticle

Dithiothreitol Enhances Arsenic Trioxide-Induced Apoptosis in NB4 Cells

Jia-Ran Gurr, Da-Tian Bau, Fount Liu, Shugene Lynn and Kun-Yan Jan
Molecular Pharmacology July 1, 1999, 56 (1) 102-109; DOI: https://doi.org/10.1124/mol.56.1.102

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Research ArticleArticle

Dithiothreitol Enhances Arsenic Trioxide-Induced Apoptosis in NB4 Cells

Jia-Ran Gurr, Da-Tian Bau, Fount Liu, Shugene Lynn and Kun-Yan Jan
Molecular Pharmacology July 1, 1999, 56 (1) 102-109; DOI: https://doi.org/10.1124/mol.56.1.102
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