Reactive Oxygen Species Are Not Required for an Arsenic Trioxide-induced Antioxidant Response or Apoptosis

• Published in: The Journal of biological chemistry Vol. 284; no. 19; pp. 12886 - 12895
• Main Authors: Morales, Alejo A., Gutman, Delia, Cejas, Pedro J., Lee, Kelvin P., Boise, Lawrence H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Apoptosis - drug effects; Arsenic Trioxide; Arsenicals - pharmacology; Blotting, Western; Butylated Hydroxyanisole - pharmacology; Gene Expression Profiling; Growth Inhibitors - pharmacology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; NF-E2-Related Factor 2 - antagonists & inhibitors; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Oxides - pharmacology; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Subcellular Fractions
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M806546200

Arsenicals are both environmental carcinogens as well as therapeutic agents for the treatment of trypanosomiasis and more recently cancer. Arsenic trioxide (ATO) has been successfully used for the treatment of acute promyelocytic leukemia (APL) and has activity in multiple myeloma (MM). While signaling events associated with carcinogenesis have been well studied, it still remains to be determined which of these events are involved in anti-cancer signaling. To better define this response, gene expression profiling following ATO treatment of four MM cell lines was performed. The pattern was consistent with a strong antioxidative response, particularly of genes activated by Nrf2. While Nrf2 is expressed constitutively at the mRNA level, the protein is not detected in untreated cells. Consistent with inactivation of Keap1, Nrf2 protein is stabilized and present in the nucleus within 6 h of ATO treatment. Despite the activation of this antioxidative response, ROS may not be important in ATO-induced death. Inhibition of ATO-induced ROS with butylated hydroxyanisole (BHA) does not affect Nrf2 activation or cell death. Moreover, silencing Nrf2 had no effect on ATO-induced apoptosis. Together these data suggest that ROS is not important in the induction of the antioxidative response or cellular death by ATO.