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.
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.
Kajiguchi
T
T
The First Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yamamoto
K
K
Hossain
K
K
Akhand
A A
AA
Nakashima
I
I
Naoe
T
T
Saito
H
H
Emi
N
N
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002908:Chronic Disease; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D020014:K562 Cells; D007951:Leukemia, Myeloid; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010087:Oxides / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077237:Arsenic Trioxide