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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2844-2853
Phenylarsine Oxide Blocks Interleukin-1 -Induced Activation of
the Nuclear Transcription Factor NF- B, Inhibits
Proliferation, and Induces Apoptosis of Acute Myelogenous Leukemia
Cells
Zeev Estrov,
Sunil K. Manna,
David Harris,
Quin Van,
Elihu H. Estey,
Hagop M. Kantarjian,
Moshe Talpaz, and
Bharat B. Aggarwal
From the Departments of Bioimmunotherapy, Molecular Oncology, and
Leukemia, The University of Texas M. D. Anderson Cancer Center,
Houston, TX.
Arsenic compounds have recently been shown to induce high rates of
complete remission in patients with acute promyelocytic leukemia (APL).
One of these compounds, As2O3, induces
apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective
against other forms of acute myelogenous leukemia (AML), we studied the
membrane-permeable arsenic compound phenylarsine oxide (PAO). Because
interleukin-1 (IL-1) plays a key role in AML cell proliferation,
we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines,
both of which produce IL-1 and proliferate in response to it. We
found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3
cells in a dose-dependent fashion (0.01 to 0.1 µmol/L) and that
IL-1 partially reversed this inhibitory effect. We then measured
IL-1 levels in these cells by using an enzyme-linked immunosorbent
assay and Western immunoblotting and found that PAO almost completely
abolished the production of IL-1 in these AML cells, whereas it did
not affect the production of IL-1 receptor antagonist. Because PAO
inhibits activation of the transcription factor NF- B and because
NF-B modulates an array of signals controlling cellular survival,
proliferation, and cytokine production, we also studied the effect of
PAO on NF-B activation in AML cells and found that PAO suppressed
the IL-1-induced activation of NF-B. Because inhibition of
NF-B may result in cellular apoptosis, we also tested whether PAO
may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was
caspase dependent, because it was completely blocked by the caspase
inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML
marrow cells from 7 patients with newly diagnosed AML and found that
PAO suppressed AML colony-forming cell proliferation in a
dose-dependent fashion. Taken together, our data showing that PAO is an
effective in vitro inhibitor of AML cells suggest that this compound
may have a role in future therapies for AML.
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