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 Minjie
  • Hong Defei
  • Hu Zhimin
  • Wu Weiding
  • Zhang Yuhua
Research Article

Abstract

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

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

Notes

Conflicts of interest

None

References

  1. 1.
    Costello E, Neoptolemos JP. Pancreatic cancer in 2010: new insights for early intervention and detection. Nat Rev Gastroenterol Hepatol. 2011;8:71–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Ducreux M, Boige V, Malka D. Treatment of advanced pancreatic cancer. Semin Oncol. 2007;34:S25–30.CrossRefPubMedGoogle Scholar
  4. 4.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297:267–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRefGoogle Scholar
  6. 6.
    Blaszkowsky L. Treatment of advanced and metastatic pancreatic cancer. Front Biosci. 1998;3:E214–25.CrossRefPubMedGoogle Scholar
  7. 7.
    de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (hdacs): characterization of the classical hdac family. Biochem J. 2003;370:737–49.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202.CrossRefPubMedGoogle Scholar
  9. 9.
    Feng W, Zhang B, Cai D, Zou X. Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett. 2014;347:183–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Koutsounas I, Giaginis C, Theocharis S. Histone deacetylase inhibitors and pancreatic cancer: are there any promising clinical trials? World J Gastroenterol. 2013;19:1173–81.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13:673–91.CrossRefPubMedGoogle Scholar
  12. 12.
    Bu HQ, Liu DL, Wei WT, Chen L, Huang H, Li Y, et al. Oridonin induces apoptosis in sw1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 mapk. Oncol Rep. 2014;31:975–82.PubMedGoogle Scholar
  13. 13.
    Min H, Xu M, Chen ZR, Zhou JD, Huang M, Zheng K, et al. Bortezomib induces protective autophagy through amp-activated protein kinase activation in cultured pancreatic and colorectal cancer cells. Cancer Chemother Pharmacol. 2014;74:167–76.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhen YF, Wang GD, Zhu LQ, Tan SP, Zhang FY, Zhou XZ, et al. P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol. 2014;229:1475–83.CrossRefPubMedGoogle Scholar
  15. 15.
    Elrod JW, Molkentin JD. Physiologic functions of cyclophilin d and the mitochondrial permeability transition pore. Circ J. 2013;77:1111–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34:232–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002;84:153–66.CrossRefPubMedGoogle Scholar
  18. 18.
    Javadov S, Kuznetsov A. Mitochondrial permeability transition and cell death: the role of cyclophilin d. Front Physiol. 2013;4:76.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Eckel F, Schneider G, Schmid RM. Pancreatic cancer: a review of recent advances. Expert Opin Investig Drugs. 2006;15:1395–410.CrossRefPubMedGoogle Scholar
  20. 20.
    Tsujimoto Y, Shimizu S. Role of the mitochondrial membrane permeability transition in cell death. Apoptosis. 2007;12:835–40.CrossRefPubMedGoogle Scholar
  21. 21.
    Clarke SJ, McStay GP, Halestrap AP. Sanglifehrin a acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-d at a different site from cyclosporin a. J Biol Chem. 2002;277:34793–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Sullivan PG, Thompson MB, Scheff SW. Cyclosporin a attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol. 1999;160:226–34.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shang Minjie
    • 1
    • 2
  • 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

Personalised recommendations