title: Targeting pancreatic cancer cells by a novel hydroxamate-based histone deacetylase (HDAC) inhibitor ST-3595.
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.
authors.affiliation: Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China. shangminjiezj@163.com.|Zhejiang Provincial People's Hospital, 158 Shang-tang Road, Hangzhou, Zhejiang, 310014, China. shangminjiezj@163.com.
authors.forename: Shang
authors.initials: S
authors.lastname: Minjie
authors.affiliation: Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Defei
authors.affiliation: Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhimin
authors.affiliation: Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Weiding
authors.affiliation: Department of Hepatopancreaticobiliary Surgery & Laparoscopic Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Yuhua
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009363:Neoplasm Proteins; D006655:Histone Deacetylases
keywords: Apoptosis; Gemcitabine sensitization; Histone deacetylase (HDAC) inhibitor; Mitochondrial permeability transition pore (MPTP); Pancreatic cancer; ST-3595