ABSTRACT
The induction of apoptotic cell death is a significant mechanism of tumor cells under the influence of radio-/chemotherapy, and resistance to these treatments has been linked to some cancer cell lines with a low propensity for apoptosis. The present study aimed to investigate the enhanced effects and mechanisms in apoptosis and the cycle distribution of HL-60 cells, a human leukemia cell line lacking a functional p53 protein, after combination treatment with arsenic trioxide (ATO) and irradiation (IR). Our results indicated that combined treatment led to increased cytotoxicity and apoptotic cell death in HL-60 cells, which was correlated with the activation of cdc-2 and increased expression of cyclin B, the induction of intracellular reactive oxygen species (ROS) generation, the loss of mitochondria membrane potential, and the activation of caspase-3. The combined treatment of HL-60 cells pre-treated with Z-VAD or NAC resulted in a significant reduction in apoptotic cells. In addition, activation of JNK and p38 MAPK may be involved in combined treatment-mediated apoptosis. The data suggest that a combination of IR and ATO could be a potential therapeutic strategy against p53-deficient leukemia cells.
Subject(s)
Apoptosis/drug effects , Apoptosis/radiation effects , Arsenicals/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Oxides/pharmacology , Reactive Oxygen Species/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Acetylcysteine/pharmacology , Antineoplastic Agents/pharmacology , Arsenic Trioxide , Caspase 3/metabolism , Cell Cycle/drug effects , Cell Cycle/radiation effects , Cell Cycle Proteins/metabolism , Cell Survival/drug effects , Cell Survival/radiation effects , Cyclins/metabolism , DNA Fragmentation/drug effects , DNA Fragmentation/radiation effects , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , F-Box Proteins/metabolism , F-Box-WD Repeat-Containing Protein 7 , HL-60 Cells , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/radiation effects , Models, Biological , Phosphorylation/drug effects , Phosphorylation/radiation effects , Poly(ADP-ribose) Polymerases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Signal Transduction/radiation effects , Tumor Stem Cell Assay , Ubiquitin-Protein Ligases/metabolism , X-Rays , bcl-2-Associated X Protein/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
Apoptosis is a common mode of cell death after exposure of tumor cells to radiation and/or chemotherapy. The factors that determine the rate of induction of apoptosis are generally related to the functioning of cell cycle checkpoints. In the present study, we investigated the involvement of several genes in cell cycle redistribution and induction of apoptosis in U937 cells after low and high doses of radiation. Activation of CDC2 was observed after both low and high doses of radiation in U937 cells that underwent apoptosis. Expression of CDK2, CDC2 and cyclin A was induced rapidly in the process of radiation-induced apoptosis. In addition, we investigated the use of a clinically relevant dose of radiation to promote As2O3-induced apoptosis in U937 cells. We found that combining radiation and As2O3 may be a new and more effective means of cancer treatment.
