Arsenic trioxide: mechanisms of action.
The chimeric protein encoded by the PML-RAR alpha gene that is pathognomonic of acute promyelocytic leukemia (APL) causes the arrest of myeloid cell development at the promyelocyte stage, leading to an accumulation of abnormal promyelocytes in the bone marrow. Differentiation therapy with all-trans retinoic acid (ATRA) is used routinely in patients with APL, but ATRA is not the only agent in clinical use that promotes differentiation of the abnormal clone. Arsenic trioxide (ATO) has been shown to cause degradation of PML-RAR alpha, promoting differentiation. APL cells are extremely sensitive to ATO, which has shown good clinical activity at low doses in patients with relapsed APL. However, degradation of PML-RAR alpha may not be wholly responsible for the great sensitivity of APL cells to ATO, which also acts through the intracellular environment to influence apoptosis, differentiation, growth arrest, and angiogenesis. ATO can act at several points in mitochondrially induced apoptosis, including degradation of peroxides and interaction with glutathione (GSH)-related enzymes. Subclones that are resistant to ATO have been used to demonstrate that sensitivity can be restored by reducing the cellular GSH content. GSH can be reduced using agents such as buthionine sulfoximine (BSO) and ascorbic acid. The key factors that determine the ATO sensitivity of cells and control ATO-induced apoptosis have not yet been defined. It has been proposed that ATO acts through activation of Jun N-terminal kinase (JNK), activator protein-1, and inhibition of dual-specificity phosphatases, and evidence is accumulating that JNK activation is an important event in arsenic-induced apoptosis. Further research is required to determine the exact pathways through which the cytotoxic actions of ATO are mediated.
Davison
Kelly
K
Lady Davis Institute, McGill University, Montreal, Quebec, Canada.
Mann
Koren K
KK
Miller
Wilson H
WH
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D002454:Cell Differentiation; D002455:Cell Division; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D009389:Neovascularization, Pathologic; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010087:Oxides / Q000627:therapeutic use*; D012008:Recurrence
D000970:Antineoplastic Agents; D001152:Arsenicals; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D005978:Glutathione; D000077237:Arsenic Trioxide