title: It's about time: scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells.
abstract: Chemotherapeutic treatment with combinations of drugs is front-line therapy for many types of cancer. Combining drugs which target different signaling pathways often lessens adverse side effects while increasing the efficacy of treatment and reducing patient morbidity. A defined scheduling protocol is described by which histone deacetylase inhibitors (HDIs) facilitate the cytotoxic effectiveness of the topoisomerase I inhibitor camptothecin in the killing of tumor cells. Breast and lung cancer cell lines were treated with camptothecin and sodium butyrate (NaB) or suberoylanilide hydroxamic acid on the day of, the day before, or the day after camptothecin addition. Depending on the time of addition, NaB-treated cells displayed a spectrum of responses from protection to sensitization, indicating the critical nature of timing in the use of HDIs. The IC80 (72-hour assay) dose of 100 nmol/L camptothecin could be lowered to 15 nmol/L camptothecin while maintaining or surpassing cell killing of the single agent if combined with an HDI added 24 to 48 hours after camptothecin. Experiments determined that cells arrested in G2-M by camptothecin were most sensitive to subsequent HDI addition. Western blot analysis indicated that in camptothecin-arrested cells, NaB decreases cyclin B levels, as well as the levels of the antiapoptotic proteins XIAP and survivin. These findings suggest that reducing the levels of these critical antiapoptotic factors may increase the efficacy of topoisomerase I inhibitors in the clinical setting if given in a sequence that does not prevent or inhibit tumor cell progression through the S phase.
authors.affiliation: Graduate Center for Toxicology and Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bevins
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Zimmer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002087:Butyrates / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D000077022:Survivin; D059004:Topoisomerase I Inhibitors; D000077337:Vorinostat; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: C107489:BIRC5 protein, human; D002087:Butyrates; D019926:Cyclin B; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D059004:Topoisomerase I Inhibitors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077337:Vorinostat; D002166:Camptothecin