© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 9, 772-778,
May 5, 1999
© 1999 Oxford University Press
REPORTS |
Apoptosis and Growth Inhibition in Malignant Lymphocytes After Treatment With Arsenic Trioxide at Clinically Achievable Concentrations
Affiliations of authors: X.-H. Zhu, Y.-L. Shen, X. Cai, P.-M. Jia, W. Tang, G.-Y. Shi, Z.-Y. Wang, S.-J. Chen, Z. Chen, G.-Q. Chen, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, People's Republic of China; Y. Jing, J. Dai, S. Waxman, Division of Neoplastic Diseases, Department of Medicine, Mount Sinai Medical Center, New York, NY; Y. Huang, Y.-P. Sun, Department of Biology, Shanghai Second Medical University; T.-D. Zhang, First Affiliated Hospital of Harbin Medical University, People's Republic of China.
Correspondence to:Samuel Waxman, M.D., Division of Neoplastic Diseases, Department of Medicine, Mount Sinai Medical Center, New York, NY 10029-6547 or Guo-Qiang Chen, M.D., Ph.D., Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197 Rui-Jin Rd. II, Shanghai 200025, People's Republic of China;
BACKGROUND: Arsenic trioxide (As2O3) can induce clinical
remission in patients with acute promyelocytic leukemia via induction of differentiation and
programmed cell death (apoptosis). We investigated the effects of As2O3
on a panel of malignant lymphocytes to determine whether growth-inhibitory and apoptotic
effects of As2O3 can be observed in these cells at clinically achievable
concentrations. METHODS: Eight malignant lymphocytic cell lines and primary cultures of
lymphocytic leukemia and lymphoma cells were treated with As2O3,
with or without dithiothreitol (DTT) or buthionine sulfoximine (BSO) (an inhibitor of
glutathione synthesis). Apoptosis was assessed by cell morphology, flow cytometry, annexin V
protein level, and terminal deoxynucleotidyl transferase labeling of DNA fragments. Cellular
proliferation was determined by 5-bromo-2'-deoxyuridine incorporation into DNA and
flow cytometry and by use of a mitotic arrest assay. Mitochondrial transmembrane potential
(
m) was measured by means of rhodamine 123 staining and flow
cytometry. Protein expression was assessed by western blot analysis or immunofluorescence.
RESULTS: Therapeutic concentrations of As2O3 (1-2 µM)
had dual effects on malignant lymphocytes: 1) inhibition of growth through adenosine
triphosphate (ATP) depletion and prolongation of cell cycle time and 2) induction of apoptosis.
As2O3-induced apoptosis was preceded by m
collapse. DTT antagonized and BSO enhanced As2O3-induced ATP
depletion, m collapse, and apoptosis. Caspase-3 activation, usually
resulting from m collapse, was not always associated with As2O3-induced apoptosis. As2O3 induced PML
(promyelocytic leukemia) protein degradation but did not modulate expression of cell
cycle-related proteins, including c-myc, retinoblastoma protein, cyclin-dependent kinase 4, cyclin
D1, and p53, or expression of differentiation-related antigens. CONCLUSIONS: Substantial
growth inhibition and apoptosis without evidence of differentiation were induced in most
malignant lymphocytic cells treated with 1-2 µM As2O3.
As2O3 may prove useful in the treatment of malignant
lymphoproliferative disorders.
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