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N-(4-hydroxyphenyl)retinamide induces growth arrest and apoptosis in HTLV-I-transformed cells

Abstract

N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that inhibits growth and induces apoptosis in many human cell lines. We explored the effects of HPR on human T-cell lymphotropic virus type I (HTLV-I)-positive and HTLV-I-negative malignant T-cell lines, most of which are resistant to all-trans retinoic acid. Clinically achievable concentrations of HPR caused a dramatic inhibition of cell proliferation, G0/G1 arrest, and massive apoptosis in all tested malignant T cells, while no effect was observed on resting or activated normal lymphocytes. Interestingly, HTLV-I-negative cell lines were significantly more sensitive to HPR compared to HTLV-I-positive and Tax-transfected cells. In HTLV-I-negative cells only, HPR-induced apoptosis was associated with ceramide accumulation, sharp decrease in mitochondrial membrane potential, and activation of caspases 8, 9 and 3, and could be partially reverted by the caspase inhibitor z-VAD suggesting that Tax protects infected cells from ceramide accumulation and caspase-mediated apoptosis. In HTLV-I-positive cells, HPR treatment rapidly induced proteasomal-mediated degradation of p21, downregulated cyclin D1, and upregulated bax protein levels. These findings support a potential therapeutic role for HPR in both HTLV-I-associated adult T-cell leukemia/lymphoma (ATL) and HTLV-I-negative peripheral T-cell lymphomas.

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Acknowledgements

We are thankful to Dr Riad Sadek and Mr Ahmad Abou-Tayyoun for their help with the statistical analysis. This work was supported by grants from the Lebanese National Council for Scientific Research, the American University of Beirut University Research Board and Medical Practice Plan, the Diana Tamari Sabbagh Foundation, the CNRS, ARECA, HERN, the Programme Franco-Libanais ‘CEDRE’, and the Eli Lilly International Foundation.

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Correspondence to N Darwiche or Ali Bazarbachi.

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Darwiche, N., Hatoum, A., Dbaibo, G. et al. N-(4-hydroxyphenyl)retinamide induces growth arrest and apoptosis in HTLV-I-transformed cells. Leukemia 18, 607–615 (2004). https://doi.org/10.1038/sj.leu.2403245

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