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Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells

Authors

  • Giovanna Tabellini,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
    Current affiliation:
    1. Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica, Università di Brescia, Brescia, Italy.
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  • Alessandra Cappellini,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
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  • Pier Luigi Tazzari,

    1. Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna, Italy
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  • Federica Falà,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
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  • Anna Maria Billi,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
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  • Lucia Manzoli,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
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  • Lucio Cocco,

    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
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  • Alberto M. Martelli

    Corresponding author
    1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia, Cell Signalling Laboratory, Università di Bologna, Italy
    2. Istituto per i Trapianti d'Organo e l'Immunocitologia del C.N.R., Sezione di Bologna c/o I.O.R., Bologna, Italy
    • Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, via Irnerio 48, 40126 Bologna, Italy.
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  • Giovanna Tabellini and Alessandra Cappellini equally contributed to this work.

Abstract

The purpose of this study was to evaluate the possible involvement of the phosphoinositide 3-kinase (PI3K)/Akt survival pathway in determining resistance to arsenic trioxide (As2O3)-induced apoptosis. We employed a HL60 cell clone (HL60AR) with a constitutively active PI3K/Akt survival pathway, as well as U937 and K562 cells. In addition, we used parental (PT) HL60 cells overexpressing a constitutively active Akt. Selective pharmacological inhibitors of the PI3K/Akt axis (LY294002, wortmannin) were employed to influence the sensitivity to As2O3. While HL60PT cells were sensitive to 2.5 μM As2O3 and died of apoptosis, HL60AR cells were resistant up to 5 μM As2O3. Treatment with either LY294002 or wortmannin lowered resistance of HL60AR cells to As2O3. Also in U937 and K562 cells, inhibitors of the PI3K/Akt axis caused a decrease in As2O3 resistance. Overexpression of constitutively active Akt in HL60PT cells caused the induction of resistance to 2.5 μM As2O3. Conversely, forced expression of a dominant negative Akt in HL60AR cells resulted in a decrease in As2O3 resistance. Moreover, HL60 cell resistance to 2.5 μM As2O3 could be significantly reduced by incubation with SN50, a peptide inhibitor selective for the NF-κB transcription factor. Taken together our findings suggest that a constitutive activation of the PI3K/Akt pathway, which is increasingly detected in some types of acute myeloid leukemia, may contribute to As2O3 resistance, most likely through NF-κB activation. Selective pharmacological inhibitors of this survival pathway, as well as of NF-κB, might be usefully employed in the future to reverse resistance to this treatment. © 2004 Wiley-Liss, Inc.

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