title: Sodium valproate, a histone deacetylase inhibitor, enhances the efficacy of vinorelbine-cisplatin-based chemoradiation in non-small cell lung cancer cells.
abstract: OBJECTIVE
  To enhance the anticancer activity of vinorelbine, cisplatin and ionizing radiation (IR) combination against non-small cell lung cancer (NSCLC) cells by co-administration of sodium valproate (VPA), a histone deacetylase inhibitor, and to elucidate molecular events underpinning treatment efficacy.
  
  
  METHODS
  The NSCLC A549 cell line was treated with cisplatin (0.2 μg/ml), vinorelbine (2 nM), VPA (1 mM) and IR (2.5 Gy) alone, or in combination. Cell proliferation, cell-cycle distribution, apoptosis, and levels of DNA double-strand breaks, activated DNA damage checkpoint kinases pCHK1, pCHK2, cell-cycle inhibitors p21CIP1/WAF1 and p27KIP1 were assessed.
  
  
  RESULTS
  VPA markedly enhanced the DNA-damaging effect of the cisplatin-vinorelbine-IR combination and induced increased DSBs, and expression of pCHK2, pCHK1, p21CIP1/WAF1 and p27KIP1. These molecular changes led to cell-cycle arrest and increased apoptosis and consequently markedly curtailed cancer cell growth.
  
  
  CONCLUSIONS
  VPA markedly enhances the anticancer activity of cisplatin-vinorelbine-IR combination. This finding has translational implications for enhancing the efficacy of anticancer treatment and for reducing side-effects by reducing doses of radiation and drugs.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel gavrilov@bgu.ac.il.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gavrilov
authors.affiliation: Institute of Oncology, Soroka University Medical Center, Beer Sheva, Israel.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Lavrenkov
authors.affiliation: Institute of Oncology, Soroka University Medical Center, Beer Sheva, Israel.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ariad
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Shraga
authors.initials: S
authors.lastname: Shany
mesh_terms: D000927:Anticonvulsants / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D000927:Anticonvulsants; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D014747:Vinblastine; D014635:Valproic Acid; D002945:Cisplatin; D000077235:Vinorelbine
keywords: Non-small cell lung cancer; cisplatin; ionizing radiation; sodium valproate; vinorelbine