Targeting pancreatic cancer cells by a novel hydroxamate-based histone deacetylase (HDAC) inhibitor ST-3595

Tumour Biol. 2015 Nov;36(11):9015-22. doi: 10.1007/s13277-015-3537-5. Epub 2015 Jun 18.


In the current study, we tested the potential anti-pancreatic cancer activity of a novel hydroxamate-based histone deacetylase (HDAC) inhibitor ST-3595. We showed that ST-3595 exerted potent anti-proliferative and cytotoxic activities against both established pancreatic cancer cell lines (PANC-1, AsPC-1, and Mia-PaCa-2), and patient-derived primary cancer cells. It was, however, generally safe to non-cancerous pancreatic epithelial HPDE6c7 cells. ST-3595-induced cytotoxicity to pancreatic cancer cells was associated with significant apoptosis activation. Reversely, the pan caspase inhibitor z-VAD-fmk and the caspase-8 inhibitor z-ITED-fmk alleviated ST-3595-mediated anti-pancreatic cancer activity in vitro. For the mechanism study, ST-3595 inhibited HDAC activity, and induced mitochondrial permeability transition pore (MPTP) opening in pancreatic cancer cells. Inhibition of MPTP, by cyclosporin A, sanglifehrin A, or by cyclophilin-D (Cyp-D) siRNA knockdown, dramatically inhibited ST-3595-induced pancreatic cancer cell apoptosis. Meanwhile, we found that a low concentration of ST-3595 dramatically sensitized gemcitabine-induced anti-pancreatic cancer cell activity in vitro. In vivo, ST-3595 oral administration inhibited PANC-1 xenograft growth in nude mice, and this activity was further enhanced when in combination with gemcitabine. In summary, the results of this study suggest that targeting HDACs by ST-3595 might represent as a novel and promising anti-pancreatic cancer strategy.

Keywords: Apoptosis; Gemcitabine sensitization; Histone deacetylase (HDAC) inhibitor; Mitochondrial permeability transition pore (MPTP); Pancreatic cancer; ST-3595.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage*
  • Mice
  • Mitochondrial Membrane Transport Proteins / drug effects*
  • Mitochondrial Permeability Transition Pore
  • Neoplasm Proteins / biosynthesis
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Neoplasm Proteins
  • Histone Deacetylases