Arsenic trioxide modulates DNA synthesis and apoptosis in lung carcinoma cells.
Arsenic trioxide, the trade name Trisenox, is a drug used to treat acute promyleocytic leukemia (APL). Studies have demonstrated that arsenic trioxide slows cancer cells growth. Although arsenic influences numerous signal-transduction pathways, cell-cycle progression, and/or apoptosis, its apoptotic mechanisms are complex and not entirely delineated. The primary objective of this research was to evaluate the effects of arsenic trioxide on DNA synthesis and to determine whether arsenic-induced apoptosis is mediated via caspase activation, p38 mitogen-activated protein kinase (MAPK), and cell cycle arrest. To achieve this goal, lung cancer cells (A549) were exposed to various concentrations (0, 2, 4, 6, 8, and 10 microg/mL) of arsenic trioxide for 48 h. The effect of arsenic trioxide on DNA synthesis was determined by the [3H]thymidine incorporation assay. Apoptosis was determined by the caspase-3 fluorescein isothiocyanate (FITC) assay, p38 MAP kinase activity was determined by an immunoblot assay, and cell-cycle analysis was evaluated by the propidium iodide assay. The [3H]thymidine-incorporation assay revealed a dose-related cytotoxic response at high levels of exposure. Furthermore, arsenic trioxide modulated caspase 3 activity and induced p38 MAP kinase activation in A549 cells. However, cell-cycle studies showed no statistically significant differences in DNA content at subG1 check point between control and arsenic trioxide treated cells.
Walker
Alice M
AM
Molecular Toxicology Research Laboratory, NIH RCMI-Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, MS 39217, USA. alice.m.walker@jsums.edu
Stevens
Jacqueline J
JJ
Ndebele
Kenneth
K
Tchounwou
Paul B
PB
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004261:DNA Replication / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001152:Arsenicals; D010087:Oxides; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D000077237:Arsenic Trioxide; D013936:Thymidine