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Review
. 2010 Jul-Sep;24(4-5):191-9.
doi: 10.1016/j.blre.2010.04.001. Epub 2010 May 15.

Arsenic trioxide - An old drug rediscovered

Ashkan Emadi  1 , Steven D Gore
Affiliations
Review

Arsenic trioxide - An old drug rediscovered

Ashkan Emadi et al. Blood Rev. 2010 Jul-Sep.

Abstract

Over the last 17 years, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (As(2)O(3)) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, the role of As(2)O(3) in front-line therapy is under investigation. Recent trials in the US have demonstrated that the addition of As(2)O(3) to standard treatment regimens improves survival outcomes in patients with APL and may allow a reduction in cytotoxic chemotherapy exposure. As(2)O(3) has also shown efficacy in other malignancies, particularly multiple myeloma and myelodysplastic syndromes. Therapeutic doses of As(2)O(3) are well tolerated, with no evidence of long-term toxicity. Adverse events include APL differentiation syndrome, electrocardiographic abnormalities, and mild elevations in liver enzymes. This review highlights trials investigating the role of As(2)O(3) in induction and consolidation for newly diagnosed APL, as well as its role in other hematologic malignancies. The chemistry, mechanisms of action, and clinical side effects of As(2)O(3) are also discussed.

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Conflict of interest statement

Conflict of interest statement

Dr. Gore: Received As2O3 from Cephalon, Inc., as part of a phase 2 trial of As2O3 in consolidation therapy of APL.

Dr. Emadi declares no conflict of interest.

Figures

Figure 1
Figure 1. As2O3 targets multiple cellular pathways
In APL cells, arsenic trioxide (As2O3) restores differentiation by degrading the PML-RARα fusion protein. However, As2O3 has additional targets that are present in multiple cancer cell types. As2O3 targets the mitochondria, decreasing the mitochondrial membrane potential (ΔΨm) via multiple specific targets including Bcl-2 and the PTPC. This change in potential results in the release of cytochrome C, which activates the caspase cascade. It also results in increased release of ROS from the mitochondria. ROS levels are increased further by As2O3 inhibition of the antioxidant enzyme GPx. As2O3 also inhibits activation of the cell-survival factor NFκB via inhibition of IKK, the kinase responsible for releasing NFκB that is sequestered in the cytoplasm. Abbreviations: APAF, apoptotic peptidase activating factor; GPx, glutathione peroxidase; IKK, IκB kinase; PTPC, permeability transition pore complex; ROS, reactive oxygen species.
Figure 2
Figure 2
Reaction of vicinal sulfhydryl groups in a protein structure with trivalent arsenic.
See this image and copyright information in PMC

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