Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance

Cell Death Dis. 2013 Feb 7;4(2):e486. doi: 10.1038/cddis.2012.210.


Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects*
  • Beclin-1
  • Cell Line, Tumor
  • Chloroquine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Histone Deacetylase Inhibitors / toxicity*
  • Humans
  • Hydroxamic Acids / toxicity*
  • Lysosomal-Associated Membrane Protein 2 / antagonists & inhibitors
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Protective Agents / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • U937 Cells
  • Vorinostat


  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Lysosomal-Associated Membrane Protein 2
  • Membrane Proteins
  • Protective Agents
  • RNA, Small Interfering
  • Vorinostat
  • Chloroquine
  • TOR Serine-Threonine Kinases