Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6

Stephanie F. MacCallum, Michael J. Groves, John James, Karen Murray, Virginia Appleyard, Alan R. Prescott, Abed A. Drbal, Anna Nicolaou, Joan Cunningham, Sally Haydock, Ian G. Ganley, Nicholas J. Westwood, Philip J. Coates, Sonia Lain, Sudhir Tauro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)
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Abstract

Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.

Original languageEnglish
Article number1275
Number of pages8
JournalScientific Reports
Volume3
DOIs
Publication statusPublished - 14 Feb 2013

Keywords

  • Histone deacetylase
  • Cell-death
  • Electron-microscopy
  • Promote longevity
  • Stress response
  • TP53 mutation
  • In-vivo
  • P53
  • Fludarabine
  • Activation

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