Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells thin express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L)

Charles Perkins, Caryn N. Kim, Guofu Fang, Kapil N. Bhalla

Research output: Contribution to journalArticlepeer-review

237 Scopus citations

Abstract

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-x(L) (HL- 60/Bcl-x(L)), 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 (ΔΨm) 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-x(L), 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.

Original languageEnglish (US)
Pages (from-to)1014-1022
Number of pages9
JournalBlood
Volume95
Issue number3
DOIs
StatePublished - Feb 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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