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

N. Darwiche, A. Hatoum, G. Dbaibo, H. Kadara, R. Nasr, G. Abou-Lteif, R. Bazzi, O. Hermine, H. de Thé, Ali Bazarbachi

Research output: Contribution to journalArticle

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-1-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.

Original languageEnglish (US)
Pages (from-to)607-615
Number of pages9
JournalLeukemia
Volume18
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

Keywords

  • HPR
  • HTLV-I
  • Leukemia
  • Lymphoma
  • Retinoids

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Darwiche, N., Hatoum, A., Dbaibo, G., Kadara, H., Nasr, R., Abou-Lteif, G., Bazzi, R., Hermine, O., de Thé, H., & Bazarbachi, A. (2004). N-(4-hydroxyphenyl)retinamide induces growth arrest and apoptosis in HTLV-I-transformed cells. Leukemia, 18(3), 607-615. https://doi.org/10.1038/sj.leu.2403245