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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 1014-1022
Arsenic induces apoptosis of multidrug-resistant human myeloid
leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or
Bcl-xL
Charles Perkins,
Caryn N. Kim,
Guofu Fang, and
Kapil N. Bhalla
From the Division of Clinical and Translational Research, Sylvester
Comprehensive Cancer Center, and the Department of Medicine, University
of Miami School of Medicine, Miami, FL.
We investigated the in vitro growth inhibitory and apoptotic effects
of clinically achievable concentrations of
As2O3 (0.5 to 2.0 µmol/L)
against human myeloid leukemia cells known to be resistant to a number
of apoptotic stimuli. These included chronic myelocytic
leukemia (CML) blast crisis K562 and HL-60/Bcr-Abl cells,
which contain p210 and p185 Bcr-Abl, respectively, and HL-60 cell types
that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-xL (HL-60/Bcl-xL), MDR (HL-60/VCR), or MRP (HL-60/AR) protein.
The growth-inhibitory IC50 values for
As2O3 treatment for 7 days against all these
cell types ranged from 0.8 to 1.5 µmol/L. Exposure to 2 µmol/L
As2O3 for 7 days induced apoptosis of all cell
types, including HL-60/Bcr-Abl and K562 cells. This was associated with the cytosolic accumulation of cyt c and preapoptotic mitochondrial events, such as the loss of inner membrane potential
(  m) and the increase in reactive oxygen species
(ROS). Treatment with As2O3 (2 µmol/L)
generated the activities of caspases, which produced the cleavage of
the BH3 domain containing proapoptotic Bid protein and poly
(ADP-ribose) polymerase. Significantly,
As2O3-induced apoptosis of HL-60/Bcr-Abl and
K562 cells was associated with a decline in Bcr-Abl protein levels,
without any significant alterations in the levels of
Bcl-xL, Bax, Apaf-1, Fas, and FasL. Although As2O3 treatment caused a marked increase in the
expression of the myeloid differentiation marker CD11b, it did not
affect Hb levels in HL-60/Bcr-Abl, K562, or HL-60/neo cells. However,
in these cells, As2O3 potently induced
hyper-acetylation of the histones H3 and H4. These findings
characterize As2O3 as a growth inhibiting and
apoptosis-inducing agent against a variety of myeloid leukemia cells
resistant to multiple apoptotic stimuli.
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