Abstract
BackgroundAcute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of all acute myloid leukemia cases. It is a blood cancer that is formed by chromosomal mutation. Each year in the United States, APL affects about 1,500 patients of all age groups and causes approximately 1.2% of cancer deaths. Arsenic trioxide (ATO) has been used successfully for treatment of APL patients, and both induction and consolidated therapy have resulted in complete remission. Recently published studies from our laboratory have demonstrated that ATO pharmacology as an anti-leukemic drug is associated with cytotoxic and genotoxic effects in leukemia cells.MethodsIn the present study, we further investigated the detailed molecular mechanism of ATO-mediated intrinsic pathway of apoptosis; using HL-60 cells as a test model. Oxidative stress was assessed by spectrophotometric measurements of MDA and GSH levels while genotoxicity was determined by single cell gel electrophoresis (Comet assay). Apoptosis pathway was analyzed by Western blot analysis of Bax, Bcl2 and caspase 3 expression, as well as immunocytochemistry and confocal imaging of Bax and Cyt c translocation and mitochondrial membrane potential depolarization.ResultsATO significantly (p < 0.05) induces oxidative stress, DNA damage, and caspase 3 activityin HL-60 cells in a dose-dependent manner. It also activated the intrinsic pathway of apoptosis by significantly modulating (p < 0.05) the expression and translocation of apoptotic molecules and decreasing the mitochondrial membrane potential in leukemia cells.ConclusionTaken together, our research demonstrated that ATO induces mitochondrial pathway of apoptosis in HL-60 cells. This apoptotic signaling is modulated via oxidative stress, DNA damage, and change in mitochondrial membrane potential, translocation and upregulation of apoptotic proteins leading programmed cell death.
Highlights
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of all acute myloid leukemia cases
Arsenic trioxide induces oxidative stress in Hl-60 cells In the present study we investigated three biomarkers of oxidative stress including lipid peroxidation as characterized by malondialdehyde (MDA) production, cellular GSH content, and Deoxyribonucleic acid (DNA) damage in HL-60 cells following treatment with different doses of ATO
Arsenic trioxide modulates apoptotic proteins expression ATO-induced oxidative stress in HL-60 cells caused an increase in the expression level of pro-apoptotic proteins (Bax and cytochrome C) and reduced the expression level of anti-apoptotic protein (Bcl-2), in a dose-dependent manner (Figure 2A)
Summary
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of all acute myloid leukemia cases. Each year in the United States, APL affects about 1,500 patients of all age groups and causes approximately 1.2% of cancer deaths. Arsenic trioxide (ATO) has been used successfully for treatment of APL patients, and both induction and consolidated therapy have resulted in complete remission. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), which causes approximately 1.2% of cancer deaths in USA [1,2]. APL is a blood cancer that affects all age groups of people and strikes about 1,500 patients in the United States each year [3]. Many therapeutic advances such as combined chemotherapy and hematopoietic stem cell transplantation have been made to improve the survival rate of APL patients, a higher proportion of patients relapse and do not undergo complete remission. Because of the growing evidence of resistance to ATRA treatment of APL patients [6], the U.S Food and Drug Administration (FDA) approved arsenic trioxide (ATO) for APL patient treatment in September 2000 on the basis of several human clinical trials showing very promising results [7]
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