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.
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References
Costello E, Neoptolemos JP. Pancreatic cancer in 2010: new insights for early intervention and detection. Nat Rev Gastroenterol Hepatol. 2011;8:71–3.
Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605–17.
Ducreux M, Boige V, Malka D. Treatment of advanced pancreatic cancer. Semin Oncol. 2007;34:S25–30.
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.
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.
Blaszkowsky L. Treatment of advanced and metastatic pancreatic cancer. Front Biosci. 1998;3:E214–25.
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.
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.
Feng W, Zhang B, Cai D, Zou X. Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett. 2014;347:183–90.
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.
Falkenberg KJ, Johnstone RW. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 2014;13:673–91.
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.
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.
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.
Elrod JW, Molkentin JD. Physiologic functions of cyclophilin d and the mitochondrial permeability transition pore. Circ J. 2013;77:1111–22.
Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34:232–7.
Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie. 2002;84:153–66.
Javadov S, Kuznetsov A. Mitochondrial permeability transition and cell death: the role of cyclophilin d. Front Physiol. 2013;4:76.
Eckel F, Schneider G, Schmid RM. Pancreatic cancer: a review of recent advances. Expert Opin Investig Drugs. 2006;15:1395–410.
Tsujimoto Y, Shimizu S. Role of the mitochondrial membrane permeability transition in cell death. Apoptosis. 2007;12:835–40.
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.
Sullivan PG, Thompson MB, Scheff SW. Cyclosporin a attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol. 1999;160:226–34.
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Minjie, S., Defei, H., Zhimin, H. et al. Targeting pancreatic cancer cells by a novel hydroxamate-based histone deacetylase (HDAC) inhibitor ST-3595. Tumor Biol. 36, 9015–9022 (2015). https://doi.org/10.1007/s13277-015-3537-5
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DOI: https://doi.org/10.1007/s13277-015-3537-5