Publication

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

MacCallum, S.
; 
Groves, M.J.
; 
James, J.
; 
Murray, K.
; 
Appleyard, V.
; 
Prescott, A.R.
; 
Drbal, Abed Alnaser A.A.
; 
Nicolaou, Anna
; 
Cunningham, J.
; 
Haydock, S.
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Publication Date
2013-02-14
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Keywords
Drug development, Chronic lymphocytic leukaemia, Macroautophagy, Tenovin-6, Tnv-6, Anti-neoplastic activity
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Peer-Reviewed
Yes
Open Access status
closedAccess
Accepted for publication
2013-01-23
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Life Sciences Publications
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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.
URI
http://hdl.handle.net/10454/7250
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Citation
MacCallum SF, Groves MJ, James J et al (2013) Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6. Scientific Reports 3: 1275.
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Link to Version of Record
https://doi.org/10.1038/srep01275
Type
Article
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