title: Valproic acid overcomes hypoxia-induced resistance to apoptosis.
abstract: Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown             to be an effective tool in cancer treatment. Although its ability to induce apoptosis             has been described in many cancer types, the data come from experiments performed             in normoxic (21% O2) conditions only. Therefore, we questioned whether VPA would             be equally effective under hypoxic conditions (1% O2), which is known to induce             resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS,             plus one cisplatin-resistant subline derived from each of the two original sensitive             lines. All were treated with VPA and incubated under hypoxic conditions. Measurement             of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling             revealed that VPA was even more effective under hypoxic conditions. We show here             that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could             be overcome using VPA. We also demonstrated that apoptosis pathways induced by             VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis             proceeds through the mitochondrial pathway, not the extrinsic pathway (under both             normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis             or influence bid cleavage. Our data demonstrated that VPA is more efficient in             triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance             to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma             (NBL) treatment.
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Medical                     School, Charles University and University Hospital Motol, V Úvalu 84,                     150 00 Prague 5, Czech Republic.
authors.forename: Šimon
authors.initials: Š
authors.lastname: Cipro
authors.forename: Jana
authors.initials: J
authors.lastname: Hřebačková
authors.forename: Jan
authors.initials: J
authors.lastname: Hraběta
authors.forename: Jitka
authors.initials: J
authors.lastname: Poljaková
authors.forename: Tomáš
authors.initials: T
authors.lastname: Eckschlager
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014635:Valproic Acid; C505530:CASP8 protein, human; D053181:Caspase 8; D002945:Cisplatin