Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
101
Journal Issue
13
Pages
4578-4583
Date Issued
2004
Author(s)
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.
SDGs
Other Subjects
arsenic; bryostatin 1; phorbol 13 acetate 12 myristate; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide phosphate oxidase; antibacterial activity; antineoplastic activity; article; cancer cell; cell death; controlled study; cytotoxicity; drug potentiation; enzyme activation; enzyme activity; gene expression profiling; genetic engineering; human; human cell; leukocyte; myeloid leukemia; priority journal; promyelocytic leukemia; RNA interference; Antineoplastic Agents; Arsenic; Cell Line, Tumor; Cell Survival; HL-60 Cells; Humans; Leukemia, Myeloid; NADPH Oxidase; Reactive Oxygen Species; U937 Cells
Type
journal article