Tumor Biology

, Volume 36, Issue 11, pp 9015–9022 | Cite as

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

  • Shang MinjieEmail author
  • Hong Defei
  • Hu Zhimin
  • Wu Weiding
  • Zhang Yuhua
Research Article


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.


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


Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shang Minjie
    • 1
    • 2
    Email author
  • Hong Defei
    • 1
  • Hu Zhimin
    • 1
  • Wu Weiding
    • 1
  • Zhang Yuhua
    • 1
  1. 1.Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive SurgeryZhejiang Provincial People’s HospitalHangzhouChina
  2. 2.Zhejiang Provincial People’s HospitalHangzhouChina

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