Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

Autophagy. 2010 Nov;6(8):1057-65. doi: 10.4161/auto.6.8.13365.

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Autophagy*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / ultrastructure
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum / ultrastructure
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / ultrastructure
  • Macrolides / pharmacology
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Phagosomes / ultrastructure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Stress, Physiological / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Vorinostat

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Macrolides
  • Microtubule-Associated Proteins
  • light chain 3, human
  • 3-methyladenine
  • Vorinostat
  • bafilomycin A1
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Adenine