Arsenic trioxide as an inducer of apoptosis and loss of PML/RARα protein in acute promyelocytic leukemia cells

Wenlin Shao, Mirco Fanelli, Fabiana F. Ferrara, Roberta Riccioni, Angelika Rosenauer, Kelly Davison, William W. Lamph, Samuel Waxman, Pier Giuseppe Pelicci, Francesco Lo Coco, Giuseppe Avvisati, Ugo Testa, Cesare Peschle, Carlo Gambacorti-Passerini, Clara Nervi, Wilson H. Miller

Research output: Contribution to journalArticlepeer-review

Abstract

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/RARα 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/RARα 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.

Original languageEnglish
Pages (from-to)124-133
Number of pages10
JournalJournal of the National Cancer Institute
Volume90
Issue number2
Publication statusPublished - Jan 21 1998

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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