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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2102-2111
Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell
Apoptosis Via a Hydrogen Peroxide-Dependent Pathway
Yongkui Jing,
Jie Dai,
Ruth M.E. Chalmers-Redman,
Willam G. Tatton, and
Samuel Waxman
From the Rochelle Belfer Chemotherapy Foundation Laboratory, Division
of Neoplastic Diseases, Department of Medicine, and the Department of
Neurology, Mount Sinai Medical Center, New York, NY.
Low concentrations of As2O3 ( 1 µmol/L)
induce long-lasting remission in patients with acute promyelocytic
leukemia (APL) without significant myelosuppressive side effects.
Several groups, including ours, have shown that 0.5 to 1 µmol/L
As2O3 induces apoptosis in APL-derived NB4
cells, whereas other leukemic cells are resistant to
As2O3 or undergo apoptosis only in response to greater than 2 µmol/L As2O3. In this report,
we show that the ability of As2O3 to induce
apoptosis in leukemic cells is dependent on the activity of the enzymes
that regulate cellular H2O2 content. Thus, NB4
cells have relatively low levels of glutathione peroxidase (GPx) and
catalase and have a constitutively higher H2O2
content than U937 monocytic leukemia cells. Glutathione-S-transferase  (GST), which is important for cellular efflux of
As2O3, is also low in NB4 cells. Moreover,
As2O3 further inhibits GPX activity and
increases cellular H2O2 content in NB4 but not
in U937 cells. Selenite pretreatment of NB4 cells increases the
activity of GPX, lowers cellular H2O2 levels,
and renders NB4 cells resistant to 1 µmol/L
As2O3. In contrast, concentrations of
As2O3 that alone are not capable of inducing
apoptosis in NB4 cells induce apoptosis in the presence of the GPx
inhibitor mercaptosuccinic acid. Similar effects are observed by
modulating the activity of catalase with its inhibitor, aminotriazol.
More important from a therapeutic point of view, U937 and HL-60 cells,
which require high concentrations of As2O3 to
undergo apoptosis, become sensitive to low, clinically acceptable
concentrations of As2O3 when cotreated with
these GPx and catalase inhibitors. The induction of apoptosis by
As2O3 involves an early decrease in cellular
mitochondrial membrane potential and increase in
H2O2 content, followed by cytochrome c release, caspase 3 activation, DNA fragmentation, and the classic morphologic changes of apoptosis.
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