Sustained activation of c-jun-terminal kinase (JNK) is closely related to arsenic trioxide-induced apoptosis in an acute myeloid leukemia (M2)-derived cell line, NKM-1.

Abstract

High concentrations (greater than 5 microM) of arsenic trioxide (As(2)O(3)) have been reported to be able to induce apoptosis in several malignant cells. We explored cell lines in which apoptosis was induced with a therapeutic concentration (1-2 microM) of As(2)O(3), and found that 1 microM of As(2)O(3) induced apoptosis in the NKM-1 cell line, which was established from a patient with acute myeloid leukemia (M2). Apoptosis induced by 1 microM of As(2)O(3) in NKM-1 cells was accompanied by an increased cellular content of H(2)O(2), a decreased mitochondrial membrane potential (Deltapsim), and activation of caspase-3. C-Jun-terminal kinase (JNK) was activated only in NKM-1 cells and arsenic-sensitive NB4 cells, but not in arsenic-insensitive HL-60 cells. Activation of JNK in NKM-1 was sustained from 6 to 24 h after As(2)O(3) treatment, and preceded changes in cellular H(2)O(2), Deltapsim, and caspase-3 activation. Moreover, addition of a JNK inhibitor reduced the percentage of apoptotic cells after the As(2)O(3) treatment. Taken together, in the M2 cell line NKM-1, 1 microM of As(2)O(3) induced sustained activation of JNK and apoptosis. This finding may provide a basis to select a subgroup other than acute promyelocytic leukemia, which can benefit from As(2)O(3) treatment.

• Authors: T Kajiguchi, K Yamamoto, K Hossain, A A Akhand, I Nakashima, T Naoe, H Saito, N Emi
• Journal: Leukemia (Leukemia) Vol. 17 Issue 11 Pg. 2189-95 (Nov 2003) ISSN: 0887-6924 [Print] England
• PMID: 12931215 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Arsenicals
• Oxides
• Reactive Oxygen Species
• Hydrogen Peroxide
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Caspase 3
• Caspases
• Arsenic Trioxide

Topics

• Acute Disease
• Antineoplastic Agents (toxicity)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals
• Caspase 3
• Caspases (metabolism)
• Chronic Disease
• Enzyme Activation
• Humans
• Hydrogen Peroxide (metabolism)
• Intracellular Membranes (drug effects, physiology)
• JNK Mitogen-Activated Protein Kinases
• K562 Cells
• Leukemia, Myeloid
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Oxides (toxicity)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured