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  • Title: Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L).
    Author: Perkins C, Kim CN, Fang G, Bhalla KN.
    Journal: Blood; 2000 Feb 01; 95(3):1014-22. PubMed ID: 10648417.
    Abstract:
    We investigated the in vitro growth inhibitory and apoptotic effects of clinically achievable concentrations of As(2)O(3) (0.5 to 2.0 micromol/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-x(L) (HL-60/Bcl-x(L)), MDR (HL-60/VCR), or MRP (HL-60/AR) protein. The growth-inhibitory IC(50) values for As(2)O(3) treatment for 7 days against all these cell types ranged from 0.8 to 1.5 micromol/L. Exposure to 2 micromol/L As(2)O(3) 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 (DeltaPsim) and the increase in reactive oxygen species (ROS). Treatment with As(2)O(3) (2 micromol/L) generated the activities of caspases, which produced the cleavage of the BH3 domain containing proapoptotic Bid protein and poly (ADP-ribose) polymerase. Significantly, As(2)O(3)-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-x(L), Bax, Apaf-1, Fas, and FasL. Although As(2)O(3 )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, As(2)O(3 )potently induced hyper-acetylation of the histones H3 and H4. These findings characterize As(2)O(3) as a growth inhibiting and apoptosis-inducing agent against a variety of myeloid leukemia cells resistant to multiple apoptotic stimuli.
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