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Acute Leukemias

Reactive oxygen species mediate N-(4-hydroxyphenyl)retinamide-induced cell death in malignant T cells and are inhibited by the HTLV-I oncoprotein Tax

Leukemia volume 21, pages 261–269 (2007)Cite this article

Abstract

N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that inhibits growth of many human tumor cells, including those resistant to natural retinoids. HPR is an effective chemopreventive agent for prostate, cervix, breast, bladder, skin and lung cancers, and has shown promise for the treatment of neuroblastomas. We have previously shown that HPR inhibits proliferation and induces apoptosis of human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia (ATL) and HTLV-I-negative malignant T cells, whereas no effect is observed on normal lymphocytes. In this report, we identified HPR-induced reactive oxygen species (ROS) generation as the key mediator of cell cycle arrest and apoptosis of malignant T cells. HPR treatment of HTLV-I-negative malignant T cells was associated with a rapid and progressive ROS accumulation. Pre-treatment with the antioxidants vitamin C and dithiothreitol inhibited ROS generation, prevented HPR-induced ceramide accumulation, cell cycle arrest, cytochrome c release, caspase-activation and apoptosis. Therefore, anti-oxidants protected malignant T cells from HPR-induced growth inhibition. The expression of the HTLV-I oncoprotein Tax abrogated HPR-induced ROS accumulation in HTLV-I-infected cells, which explains their lower sensitivity to HPR. Defining the mechanism of free radical induction by HPR may support a potential therapeutic role for this synthetic retinoid in ATL and HTLV-I-negative T-cell lymphomas.

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Acknowledgements

This work was supported by grants from the Lebanese National Council for Scientific Research and the American University of Beirut University Research Board and Medical Practice Plan.

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Authors and Affiliations

  1. Department of Biology, American University of Beirut, Beirut, Lebanon

    N Darwiche & G Abou-Lteif

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

    A Bazarbachi

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  1. N Darwiche
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  2. G Abou-Lteif
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  3. A Bazarbachi
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Correspondence to N Darwiche or A Bazarbachi.

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Darwiche, N., Abou-Lteif, G. & Bazarbachi, A. Reactive oxygen species mediate N-(4-hydroxyphenyl)retinamide-induced cell death in malignant T cells and are inhibited by the HTLV-I oncoprotein Tax. Leukemia 21, 261–269 (2007). https://doi.org/10.1038/sj.leu.2404472

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