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Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma

Abstract

HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition of cell proliferation and induction of apoptosis in fresh ATL cells, HTLV-I transformed and HTLV-I-negative malignant T cells, while normal resting or activated T lymphocytes were resistant. Combination of PS-341 and doxorubicin or etoposide resulted in an additive growth inhibition. In HTLV-I-negative malignant cells, PS-341 treatment significantly downregulated the antiapoptotic protein X-IAP and to a lesser extent c-IAP-1 and bcl-XL and resulted in caspase-dependent apoptosis. In HTLV-I transformed cells, the inhibition of the proteasomal degradation of Tax by PS-341 likely explains the relative protection of HTLV-I infected cells against caspase-dependent apoptosis. PS-341 treatment of these cells stabilized IκBα, IκBβ, IκBɛ, p21, p27 and p53 proteins and selectively inhibited Rel-A DNA binding NF-κB complexes. In both HTLV-I-positive and -negative cells, PS-341 treatment induced ceramide accumulation that correlated with apoptosis. We conclude that PS-341 affects multiple pathways critical for the survival of HTLV-I-positive and -negative malignant T cells supporting a potential therapeutic role for PS-341 in both ATL and HTLV-I-negative T-cell lymphomas, whether alone or in combination with chemotherapy.

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Acknowledgements

We thank Dr Kamal Badr for critical reading of this manuscript. The expert assistance from the personnel of the core laboratory facilities of the American University of Beirut is greatly appreciated. This paper is supported by the American University of Beirut University Research Board and Medical Practice Plan, the Lebanese National Council for Scientific Research, the Diana Tamari Sabbagh Foundation, the CNRS, ARECA, HERN, the Eli Lilly International Foundation and the Lady TATA memorial trust.

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Correspondence to Olivier Hermine or Ali Bazarbachi.

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Nasr, R., El-Sabban, M., Karam, JA. et al. Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene 24, 419–430 (2005). https://doi.org/10.1038/sj.onc.1208212

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