title: Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer.
abstract: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype in need of better therapies. Histone deacetylase inhibitors (HDIs) promote increased lysine acetylation in nucleosomal histones and are thought to relax chromatin, thereby allowing increased access of transcription factors and DNA damaging agents alike to DNA. We studied whether two HDIs, belinostat and romidepsin, could be effectively combined with cisplatin or etoposide (VP-16) for SCLC cells. Analysis of cell survival and synergy was performed using CalcuSyn mathematical modeling to calculate a combination index. Immunostaining of γH2AX was performed to evaluate persistence of DNA damage following simultaneous or sequential exposure. Based on CalcuSyn modeling, HDIs synergized with DNA damaging agents only when added simultaneously. An additive-to-antagonistic effect was seen with HDI pretreatment for 24 h or with addition after cisplatin or etoposide. Furthermore, pretreatment with HDIs resulted in normalization of cell cycle and reduced PARP degradation as compared with simultaneous treatment. The increase in γH2AX phosphorylation confirmed that simultaneous but not sequential treatment enhanced double-stranded DNA breaks. These results suggest that DNA relaxation is not required for synergy of HDIs with DNA damaging agents, and that scheduling of drug administration will be critical for rational development of clinical protocols.
authors: National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Victoria L
authors: VL
authors: Luchenko
authors: Crystal D
authors: CD
authors: Salcido
authors: Yongwei
authors: Y
authors: Zhang
authors: Keli
authors: K
authors: Agama
authors: Edina
authors: E
authors: Komlodi-Pasztor
authors: Robert F
authors: RF
authors: Murphy
authors: Giuseppe
authors: G
authors: Giaccone
authors: Yves
authors: Y
authors: Pommier
authors: Susan E
authors: SE
authors: Bates
authors: Lyuba
authors: L
authors: Varticovski
mesh_terms: D000107:Acetylation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D047630:Depsipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage* / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D008962:Models, Theoretical; D010766:Phosphorylation; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides; D013997:Time Factors
chemical_list: D047630:Depsipeptides; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D005047:Etoposide; C087123:romidepsin; C487081:belinostat; D002945:Cisplatin