Oxidase Enzyme is the Target for Arsenic-Induced Reactive Oxygen Species Production in Leukemia Cells

Michael A. Trush, Ph.D.
The Johns Hopkins University School of Medicine
R01ES03760 and P30ES03819

Background: Arsenic is a naturally occurring metal-like element found widely and in varied forms in the environment. Inorganic forms of arsenic are considered the most toxic and are found in drinking water, soils, and geologic formations. Humans can be exposed to arsenic in a variety of ways; however drinking contaminated water and industrial exposures are the most common. Arsenic is acutely toxic to humans at doses that generally occur through accidental or intentional poisonings. Arsenic is a known carcinogen to humans; skin cancer is the most common form of malignancy; however, other cancers of the lung, bladder, liver, kidney, and prostate can also occur following arsenic exposure. Interestingly, arsenic has been used for centuries in traditional folk remedies and today it is a component of cancer chemotherapeutic agents. Recently, much attention has been paid to the dramatic clinical efficacy of arsenic against acute promyelocytic leukemia.

Advance: Arsenic is known to induce the formation of reactive oxygen species (ROS); however, the mechanism has previously been undefined. Using gene expression profiling, interference RNA, and genetically engineered cells, these investigators determined that an enzyme required for the normal antibacterial function of white blood cells known as NADPH oxidase is the main target for arsenic-induced ROS production. NADPH oxidase can also be stimulated by a compound known as phorbol myristate. The investigators went on to show that arsenic and a clinically used analog of phorbol myristate, bryostatin 1, synergistically act to enhance ROS production.

Implication: These investigators have shown that very low levels of arsenic and bryostatin 1 can effectively kill leukemic cells. The findings identify the arsenic target of ROS production and provide a new concept for an anticancer treatment that may have decreased adverse side effects. These findings may also provide clues to the carcinogenic potential of arsenic.

Citation: Chou WC, Kie C, Kenedy AA, Jones RJ, Trush MA, Dang CV. Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci USA. 2004 Mar 30; 101(13):4578-83.