© 1998 by Oxford University Press
Journal Of The National Cancer Institute, Vol 90, 124-133, Copyright © 1998 by Oxford University Press
W Shao, M Fanelli, FF Ferrara, R Riccioni, A Rosenauer, K Davison, WW Lamph, S Waxman, PG Pelicci, F Lo Coco, G Avvisati, U Testa, C Peschle, C Gambacorti-Passerini, C Nervi and WH Miller Jr
BACKGROUND: Retinoids, which are derivatives of vitamin A, induce
differentiation of acute promyelocytic leukemia (APL) cells in vitro and in
patients. However, APL cells develop resistance to retinoic acid treatment.
Arsenic trioxide (As2O3) can induce clinical remission in patients with
APL, including those who have relapsed after retinoic acid treatment, by
inducing apoptosis (programmed cell death) of the leukemia cells. In this
study, we investigated the molecular mechanisms by which As2O3 induces
apoptosis in retinoic acid-sensitive NB4 APL cells, in retinoic
acid-resistant derivatives of these cells, and in fresh leukemia cells from
patients. METHODS: Apoptosis was assessed by means of DNA fragmentation
analyses, TUNEL assays (i.e., deoxyuridine triphosphate labeling of DNA
nicks with terminal deoxynucleotidyl transferase), and flow cytometry.
Expression of the PML/RAR alpha fusion protein in leukemia cells was
assessed by means of western blotting, ligand binding, and
immunohistochemistry. Northern blotting and ribonuclease protection assays
were used to evaluate changes in gene expression in response to retinoic
acid and As2O3 treatment. RESULTS AND CONCLUSIONS: As2O3 induces apoptosis
without differentiation in retinoic acid-sensitive and retinoic
acid-resistant APL cells at concentrations that are achievable in patients.
As2O3 induces loss of the PML/RAR alpha fusion protein in NB4 cells, in
retinoic-acid resistant cells derived from them, in fresh APL cells from
patients, and in non-APL cells transfected to express this protein. As2O3
and retinoic acid induce different patterns of gene regulation, and they
inhibit the phenotypes induced by each other. Understanding the molecular
basis of these differences in the effects of As2O3 and retinoic acid may
guide the clinical use of arsenic compounds and provide insights into the
management of leukemias that do not respond to retinoic acid.
ARTICLES
Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Department of Oncology, Montreal, Quebec, Canada.
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