Darwiche N, Hatoum A, Dbaibo G, Kadara H, Nasr R, Abou-Lteif G, Bazzi R, Hermine O, de Thé H, Bazarbachi Ali
Department of Biology, American University of Beirut, Beirut, Lebanon.
Leukemia. 2004 Mar;18(3):607-15. doi: 10.1038/sj.leu.2403245.
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, G(0)/G(1) 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 D(1), 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.
N-(4-羟基苯基)视黄酰胺（HPR）是一种合成类视黄醇，可抑制多种人类细胞系的生长并诱导其凋亡。我们探究了HPR对I型人类嗜T细胞病毒（HTLV-I）阳性和HTLV-I阴性恶性T细胞系的影响，其中大多数细胞系对全反式维甲酸具有抗性。临床可达到的HPR浓度对所有测试的恶性T细胞均产生了显著的细胞增殖抑制、G(0)/G(1)期阻滞和大量凋亡，而对静息或活化的正常淋巴细胞未观察到影响。有趣的是，与HTLV-I阳性和Tax转染细胞相比，HTLV-I阴性细胞系对HPR的敏感性显著更高。仅在HTLV-I阴性细胞中，HPR诱导的凋亡与神经酰胺积累、线粒体膜电位急剧下降以及半胱天冬酶8、9和3的激活相关，并且半胱天冬酶抑制剂z-VAD可部分逆转这种凋亡，这表明Tax可保护受感染细胞免受神经酰胺积累和半胱天冬酶介导的凋亡影响。在HTLV-I阳性细胞中，HPR处理迅速诱导蛋白酶体介导的p21降解，下调细胞周期蛋白D(1)，并上调bax蛋白水平。这些发现支持了HPR在HTLV-I相关的成人T细胞白血病/淋巴瘤（ATL）和HTLV-I阴性外周T细胞淋巴瘤中具有潜在治疗作用。
