N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

S. Bruno, F. Ghiotto, C. Tenca, A. N. Mazzarello, M. Bono, P. Luzzi, S. Casciaro, A. Recchia, A. Decensi, F. Morabito, F. Fais

Research output: Contribution to journalArticle

Abstract

The in vitro effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) on primary B-cell chronic lymphocytic leukemia (CLL) cells from previously untreated CLL patients were investigated. 4HPR promoted the intrinsic apoptotic pathway by reactive oxygen species (ROS) generation and was accompanied by drop of Mcl-1 protein expression. The latter was not attributable to transcriptional downregulation but to protein degradation mediated by jun N-terminal kinase activation, and likely by NF-kB downregulation and Noxa upregulation. CLL cells stimulated in vitro with CD40L did not increase 4HPR chemoresistance if activation was accompanied by proliferation. Intra-patient analysis confirmed that the proliferating pool of CLL cells was more sensitive to the cytotoxic action of 4HPR than the activated but resting CLL subpopulation. The different 4HPR susceptibility of the two subpopulations was associated with higher Noxa expression in proliferating CLLs. Combination experiments revealed that 4HPR strongly potentiated ABT-737 cytotoxicity, especially in proliferating CLL cells that displayed amplified chemoresistance to ABT-737 alone. Synergic cytotoxicity was also demonstrated in combination with fludarabine, in both resting and stimulated CLL samples. This study entitles 4HPR to be assayed as a chemotherapeutic adjuvant for the treatment of CLL.

Original languageEnglish
Pages (from-to)2260-2268
Number of pages9
JournalLeukemia
Volume26
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • 4HPR
  • Apoptosis
  • Chronic lymphocytic leukemia
  • Proliferation

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Bruno, S., Ghiotto, F., Tenca, C., Mazzarello, A. N., Bono, M., Luzzi, P., Casciaro, S., Recchia, A., Decensi, A., Morabito, F., & Fais, F. (2012). N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity. Leukemia, 26(10), 2260-2268. https://doi.org/10.1038/leu.2012.98