Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells

Sougat Misra, Arun Kumar Selvam, Marita Wallenberg, Aditya Ambati, András Matolcsy, Isabelle Magalhaes, Gilbert Lauter, Mikael Björnstedt

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Selective targeting of the PML/RARa oncoprotein demonstrates a successful molecular targeted therapy in acute promyelocytic leukemia (APL) with a typical t(15:17) chromosomal translocation. The zinc-thiolate coordination is critical for structural stability of zinc finger proteins, including the PML moiety of PML/RARa. Based on the known interaction of redox-active selenium compounds with thiolate ligands of zinc, we herein have investigated the abrogatory effects of selenite alone or in combination with all-trans retinoic acid on PML/RARa and the possible effects on differentiation in these cells. At pharmacological concentrations, selenite inhibited the proliferation and survival of APL originated NB4 cells. In combination with ATRA, it potentiated the differentiation of NB4 cells without any differentiating effects of its own as a single agent. Concordant with our hypothesis, PML/RARa oncoprotein expression was completely abrogated by selenite. Increased expression of RAR, PU.1 and FOXO3A transcription factors in the combined treatment suggested the plausible basis for increased differentiation in these cells. We show that selenite at clinically achievable dose targets PML/RARa oncoprotein for degradation and potentiates differentiation of promyelocytic leukemic cells in combination with ATRA. The present investigation reveals the hitherto unknown potential of selenite in targeted abrogation of PML/RARa in APL cells with prospective therapeutic value.

Original languageEnglish
Pages (from-to)74686-74700
Number of pages15
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - Jan 1 2016

Keywords

  • Acute myeloid leukemia
  • All-trans retinoic acid
  • Differentiation
  • PML/RARA
  • Selenite

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Misra, S., Selvam, A. K., Wallenberg, M., Ambati, A., Matolcsy, A., Magalhaes, I., Lauter, G., & Björnstedt, M. (2016). Selenite promotes all-trans retinoic acid-induced maturation of acute promyelocytic leukemia cells. Oncotarget, 7(46), 74686-74700. https://doi.org/10.18632/oncotarget.12531