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

• Published in: Leukemia Vol. 18; no. 3; pp. 607 - 615
• Main Authors: DARWICHE, N, HATOUM, A, DBAIBO, G, KADARA, H, NASR, R, ABOU-LTEIF, G, BAZZI, R, HERMINES, O, DE THE, H, BAZARBACHI, Ali
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.03.2004; Nature Publishing Group
• Subjects: Accumulation; Acid resistance; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bax protein; bcl-2-Associated X Protein; Biological and medical sciences; Caspase; Caspase inhibitors; Caspases - metabolism; Cell cycle; Cell Division - drug effects; Cell growth; Cell Line, Transformed; Cell proliferation; Cell Transformation, Viral; Ceramide; Cyclin D; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - metabolism; Fenretinide - pharmacology; GTP-binding protein; Hematologic and hematopoietic diseases; Human T-lymphotropic virus 1 - physiology; Humans; Internal medicine; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Lymphocytes T; Lymphoma; Medical sciences; Membrane potential; Mitochondria; Proteasomes; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; Retinoic acid; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; T-Lymphocytes - virology; Transformed cells; Tumor Cells, Cultured; Viruses; Lebanon; United States > US; Beirut Lebanon; Hematology; Transformed cell; Leukemia; Retinoid; Retroviridae; Malignant hemopathy; HPR; Cell transformation; Carcinogenesis; Lymphoma; Virus; HTLV-I; Lymphoproliferative syndrome; HTLV-I virus; retinoids; Apoptosis
• ISSN: 0887-6924; 1476-5551
• 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.