title: Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation.
abstract: Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combination, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic for thoracic cancers.
authors.affiliation: Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M Firdos
authors.initials: MF
authors.lastname: Ziauddin
authors.forename: Wen-Shuz
authors.initials: WS
authors.lastname: Yeow
authors.forename: Justin B
authors.initials: JB
authors.lastname: Maxhimer
authors.forename: Aris
authors.initials: A
authors.lastname: Baras
authors.forename: Alex
authors.initials: A
authors.lastname: Chua
authors.forename: Rishindra M
authors.initials: RM
authors.lastname: Reddy
authors.forename: Wilson
authors.initials: W
authors.lastname: Tsai
authors.forename: George W
authors.initials: GW
authors.lastname: Cole
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Dao M
authors.initials: DM
authors.lastname: Nguyen
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004827:Epilepsy / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013899:Thoracic Neoplasms / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014635:Valproic Acid; D020169:Caspases