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APL

WEB-2086 and WEB-2170 trigger apoptosis in both ATRA-sensitive and -resistant promyelocytic leukemia cells and greatly enhance ATRA differentiation potential

Leukemia volume 19, pages 390–395 (2005)Cite this article

Abstract

PAF-receptor antagonists WEB-2086 and WEB-2170 (WEBs) have been previously shown to induce differentiation in murine and human leukemia cells. The present study describes the apoptotic-differentiative effect of WEBs in all-trans-retinoic acid (ATRA)-sensitive (NB4) and -resistant (NB4-007-6 and NB4-MR4) acute promyelocytic leukemia (APL) cell lines as well as blasts from patients with t(15;17) APL. NB4 cells exposed to 0.5–1 mM WEBs underwent striking growth arrest and massive apoptosis without appreciable differentiation; IC50 values after 3-day treatment of NB4 were 0.4 and 0.25 mM for WEB-2086 and WEB-2170, respectively. WEBs induced apoptosis also in the two ATRA-resistant NB4-007-6 and NB4-MR4 cell lines and in blasts from patients with t(15;17) APL. Moreover, subapoptotic WEBs acted synergistically with low-dose (0.025–0.05 μ M) ATRA; this allowed to increase ATRA differentiation potential up to 40-fold and to improve both number and intensity of NBT-positive NB4 cells at definitely higher levels than with 1 μ M ATRA alone. The powerful antiproliferative-apoptotic activities of WEBs in vitro on ATRA-sensitive, ATRA-resistant APL cells and blasts from patients with APL as well as drug capabilities to enhance ATRA differentiation potential suggested that these agents also due to their recognized tolerability in vivo might improve, alone or in combination, clinical treatment of APL.

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Acknowledgements

This work is supported by grants from MURST (PRIN 2002, # MM06103241) and the University of Florence. AL and CC are PhD fellows; AP is a fellow of AIL (Associazione Italiana contro le Leucemie; Firenze). Authors are grateful to F Pane (Department of Biochemistry and Medical Biotechnology, Federico II University, Naples, Italy) who kindly provided primary blasts from patients with APL.

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Authors and Affiliations

  1. Department of Experimental Pathology and Oncology, University of Florence, Italy

    A Laurenzana, C Cellai & F Paoletti

  2. Department of Hematology, University of Florence, Italy

    A M Vannucchi & A Pancrazzi

  3. Department of Pharmaceutical Sciences, University of Florence, Italy

    M N Romanelli

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  1. A Laurenzana
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  2. C Cellai
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  3. A M Vannucchi
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  4. A Pancrazzi
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  5. M N Romanelli
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  6. F Paoletti
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Correspondence to F Paoletti.

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Laurenzana, A., Cellai, C., Vannucchi, A. et al. WEB-2086 and WEB-2170 trigger apoptosis in both ATRA-sensitive and -resistant promyelocytic leukemia cells and greatly enhance ATRA differentiation potential. Leukemia 19, 390–395 (2005). https://doi.org/10.1038/sj.leu.2403618

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