Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells

Wen Chien Chou, Chunfa Jie, Andrew A. Kenedy, Richard J Jones, Michael A. Trush, Chi V. Dang

Research output: Contribution to journalArticle

Abstract

Arsenic has played a key medicinal role against a variety of ailments for several millennia, but during the past century its prominence has been displaced by modern therapeutics. Recently, attention has been drawn to arsenic by its dramatic clinical efficacy against acute promyelocytic leukemia. Although toxic reactive oxygen species (ROS) induced in cancer cells exposed to arsenic could mediate cancer cell death, how arsenic induces ROS remains undefined. Through the use of gene expression profiling, interference RNA, and genetically engineered cells, we report here that NADPH oxidase, an enzyme complex required for the normal antibacterial function of white blood cells, is the main target of arsenic-induced ROS production. Because NADPH oxidase enzyme activity can also be stimulated by phorbol myristate acetate, a synergism between arsenic and the clinically used phorbol myristate acetate analog, bryostatin 1, through enhanced ROS production can be expected. We show that this synergism exists, and that the use of very low doses of both arsenic and bryostatin 1 can effectively kill leukemic cells. Our findings pinpoint the arsenic target of ROS production and provide a conceptual basis for an anticancer regimen.

Original languageEnglish (US)
Pages (from-to)4578-4583
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number13
DOIs
StatePublished - Mar 30 2004

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Myeloid Leukemia
NADPH Oxidase
Arsenic
Myeloid Cells
Reactive Oxygen Species
Tetradecanoylphorbol Acetate
Acute Promyelocytic Leukemia
Poisons
Gene Expression Profiling
Enzymes
RNA Interference
Neoplasms
Leukocytes
Cell Death

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. / Chou, Wen Chien; Jie, Chunfa; Kenedy, Andrew A.; Jones, Richard J; Trush, Michael A.; Dang, Chi V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 13, 30.03.2004, p. 4578-4583.

Research output: Contribution to journalArticle

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AU - Dang, Chi V.

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