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Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia
- Source :
- Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine. 30(3)
- Publication Year :
- 2016
-
Abstract
- Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the constitutive expression of BCR-ABL tyrosine kinase. Although successful implementation of tyrosine kinase inhibitors for the treatment of CML remain a traditional choice for molecularly targeted therapy, some patients present primary or secondary resistance to such therapy. Therefore, alternative therapeutic strategies are required to treat resistant CML cells. Accordingly, new anti-proliferative and/or pro-apoptotic compounds would be needed for clinical treatment. In the present investigation, we demonstrate that TPEN (e.g. 3 μM), a lipid-soluble metal chelator, induces apoptosis in K562 cells via a molecular cascade involving H2O2 ≫ JNK, NF-κB > c-JUN, P73 > PUMA, BAX > loss of ΔΨm > CASPASE-3 > nuclei/DNA fragmentation. Fragmentation of the nuclei and DNA are indicative of cell death by apoptosis. Remarkably, the antioxidant N-acetyl-cysteine, and inhibitors of the transcription factors CASPASE 3 and (JNK) kinase, decreased oxidative stress (OS) and cell death in these cells. This is evidenced by fluorescence microscopy, flow cytometry and immunocytochemistry for OS markers (e.g. generation of H2O2 and DJ 1 oxidation) and nuclear expression of apoptotic markers (e.g. activated caspase 3 and JNK kinase). In addition, TPEN causes no detectable damage in human peripheral blood lymphocyte cells (hPBLCs). We conclude that TPEN selectively induces apoptosis in K562 cells via an OS-mechanism. Our findings may provide insight into more effective CML anticancer therapies.
- Subjects :
- 0301 basic medicine
Adult
Male
Programmed cell death
Caspase 3
Antineoplastic Agents
Apoptosis
Biology
General Biochemistry, Genetics and Molecular Biology
Biomaterials
03 medical and health sciences
Young Adult
hemic and lymphatic diseases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Humans
Fragmentation (cell biology)
Cells, Cultured
Chelating Agents
Metals and Alloys
Myeloid leukemia
Ethylenediamines
Molecular biology
Zinc
030104 developmental biology
Cancer research
DNA fragmentation
Drug Screening Assays, Antitumor
General Agricultural and Biological Sciences
K562 Cells
Reactive Oxygen Species
Tyrosine kinase
K562 cells
Signal Transduction
Subjects
Details
- ISSN :
- 15728773
- Volume :
- 30
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
- Accession number :
- edsair.doi.dedup.....889c050dcb020198ae48c390a9490a8e