Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells.
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.
Chou
Wen-Chien
WC
Program of Human Genetics and Molecular Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Jie
Chunfa
C
Kenedy
Andrew A
AA
Jones
Richard J
RJ
Trush
Michael A
MA
Dang
Chi V
CV
D000970:Antineoplastic Agents / Q000633:toxicity; D001151:Arsenic / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid; D019255:NADPH Oxidases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020298:U937 Cells
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D001151:Arsenic