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Lymphoma

PS-341 or a combination of arsenic trioxide and interferon-α inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV-8-infected primary effusion lymphoma cells

Leukemia volume 21, pages 1792–1801 (2007)Cite this article

Abstract

Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-α (IFN-α) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-κB (NF-κB) activation. PEL cells also display an activated NF-κB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-α combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-α treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-α treatment abrogated NF-κB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-XL. Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-α in PEL patients.

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Acknowledgements

This project is supported by grants from the American University of Beirut (Medical Practice Plan and University Research Board) and from Cancéropole. RM is supported by INSERM. DA is supported by CNRS. Contributions: RAM, RK, MEES, OH, HT, RM and AB designed the experiments. RAM, RK, DA, HEH, HD, SM and RM performed the experiments. RAM, AB and RM analyzed the data. RAM, RK, MEES, MEES, OH, AG, HT, RM and AB wrote the article.

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Author notes

  1. D Arnoult and H El Hajj: These authors contributed equally to the work.

  2. R Mahieux and A Bazarbachi: These authors share senior authorship.

Authors and Affiliations

  1. Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

    R Abou-Merhi, R Khoriaty, H El Hajj, H Dbouk & A Bazarbachi

  2. CNRS U542 Hopital Paul Brousse, Villejuif, France

    D Arnoult

  3. Groupe à 5 ans de Virologie Moléculaire et de Vectorologie, Institut Pasteur, Paris, France

    S Munier

  4. Department of Human Morphology, American University of Beirut, Beirut, Lebanon

    M E El-Sabban

  5. CNRS UMR 8603 and Department of Hematology, Necker Hospital, Paris, France

    O Hermine

  6. Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, CNRS URA 3015, Institut Pasteur, Paris, France

    A Gessain & R Mahieux

  7. UMR 7151 CNRS/University of Paris 7, Paris, France

    H de Thé

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  1. R Abou-Merhi
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Correspondence to R Mahieux or A Bazarbachi.

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Abou-Merhi, R., Khoriaty, R., Arnoult, D. et al. PS-341 or a combination of arsenic trioxide and interferon-α inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV-8-infected primary effusion lymphoma cells. Leukemia 21, 1792–1801 (2007). https://doi.org/10.1038/sj.leu.2404797

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