title: Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II.
abstract: BACKGROUND
  Human pancreatic carcinoids, a type of neuroendocrine tumors, are asymptomatic and difficult to diagnose, with the effects of traditional anti-cancer therapies being limited. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was evaluated for its effects alone and in combination with receptor-targeting peptide-drug conjugate via increasing drug internalization.
  
  
  METHODS
  The in vitro and in vivo assays were used to evaluate the effects of VPA and somatostatin receptor-targeting camptothecin-somatostatin conjugate (CPT-SST).
  
  
  RESULTS
  VPA induced proliferation suppression, cell apoptosis and cell cycle arrest. VPA acts as a HDAC inhibitor to induce a decrease of HDAC4 and an increase of acetylated histone 4 (AcH4). Meanwhile, most importantly, besides activating Notch signaling, VPA was observed to stimulate the expression of somatostatin receptor type 2 (SSTR2) that has been applied for receptor-targeting therapies. This characteristic was used for a combination therapy of VPA and CPT-SST. The combination displayed much more potent anti-tumor effects on carcinoid tumor growth by increasing SSTR2 density and drug internalization in target tumor cells.
  
  
  CONCLUSIONS
  The combination of VPA and a SSTR2-targeting agent provides us a promising approach in treatment of carcinoid tumors.
authors.affiliation: a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China .|b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
authors.affiliation: a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China .
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Qian
authors.affiliation: a Department of Pharmacy , The Fifth People's Hospital of Shanghai, Fudan University , Shanghai , China .
authors.forename: Guangchun
authors.initials: G
authors.lastname: Sun
authors.affiliation: b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.
authors.forename: L Vienna
authors.initials: LV
authors.lastname: Mackey
authors.affiliation: b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.affiliation: b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
authors.affiliation: b Department of Medicine , Peptide Research Laboratories, Tulane Health Sciences Center , New Orleans , LA , USA , and.|c Department of Pharmacy , Institute of Pharmacy & Pharmacology, University of South China , Hengyang , China.
authors.forename: Cui-Yun
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010455:Peptides; D051880:Receptors, Notch; D018000:Receptors, Peptide; D017481:Receptors, Somatostatin; D012097:Repressor Proteins; C574734:SSTR2 protein, human; D014635:Valproic Acid; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002166:Camptothecin
keywords: Carcinoid; HDAC inhibitor; peptide–drug conjugate; receptor-targeting; tumor suppression; valproic acid