title: Combined effects of sulindac and suberoylanilide hydroxamic acid on apoptosis induction in human lung cancer cells.
abstract: Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. Treatment of cancer cells with HDAC blockers, such as suberoylanilide hydroxamic acid (SAHA), leads to the activation of apoptosis-promoting genes. To enhance proapoptotic efficiency, SAHA has been used in conjunction with radiation, kinase inhibitors, and cytotoxic drugs. In the present study, we show that at the suboptimal dose of 250 muM, sulindac [2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]-acetic acid] significantly enhances SAHA-induced growth suppression and apoptosis of A549 human non-small cell lung cancer cells, primarily via enhanced collapse of the mitochondrial membrane potential, release of cytochrome c, and caspase activation. Furthermore, sulindac/SAHA cotreatment induced marked down-regulation of survivin at both the mRNA and protein levels and stimulated the production of reactive oxygen species (ROS), which were blocked by the antioxidant N-acetyl-l-cysteine. Overexpression of survivin was associated with reduced sulindac/SAHA-induced apoptosis of A549 cells, whereas suppression of survivin levels with antisense oligonucleotides or small interfering RNA further sensitized cells to sulindac/SAHA-induced cell death. Our results collectively demonstrate that sulindac/SAHA-induced apoptosis is mediated by ROS-dependent down-regulation of survivin in lung cancer cells.
authors.affiliation: Laboratory of Radiation Resistance Control, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, 139-706 Nowon-Ku, Seoul, Korea.
authors.forename: Sung-Keum
authors.initials: SK
authors.lastname: Seo
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: Hyung-Chahn
authors.initials: HC
authors.lastname: Lee
authors.forename: Sang-Hyeok
authors.initials: SH
authors.lastname: Woo
authors.forename: Eun-Sung
authors.initials: ES
authors.lastname: Kim
authors.forename: Doo-Hyun
authors.initials: DH
authors.lastname: Yoo
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Rhee
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D020169:Caspases / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D011419:Propidium / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D017304:Annexin A5; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D013467:Sulindac; D011419:Propidium; D000077337:Vorinostat; D020169:Caspases; D016650:Fluorescein-5-isothiocyanate