Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death.
BACKGROUND
Non-small cell lung cancer (NSCLC) remains resistant to traditional and novel chemotherapeutic agents, relating, in part, to the activation of the antiapoptotic transcription factor NF-kappaB. We hypothesize that inhibition of NF-kappaB using BAY-11-7085 will sensitize NSCLC cells to death, induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA).


METHODS
Five tumorigenic NSCLC cell lines (A549, H157, H358, H460, H1299) were treated with nothing, SAHA, BAY-11-7085, or both compounds. Cell death was determined by crystal violet staining. p65 nuclear translocation was determined by Western blot analysis. NF-kappaB activity was determined by reporter-gene assays and by reverse transcriptase-polymerase chain reaction of the endogenous NF-kappaB-dependent gene interleukin 8. Apoptosis was determined by DNA fragmentation. Clonogenic cell survival assays were also performed. Data was analyzed with the Student t test when appropriate.


RESULTS
SAHA alone resulted in no meaningful NSCLC cell death. SAHA induced nuclear translocation of p65, which was inhibited by BAY-11-7085. SAHA significantly induced NF-kappaB-dependent transcription which was ameliorated after treatment with BAY-11-7085 (P = .01). Combined SAHA and BAY-11-7085 induced significantly more apoptosis and cell death than either drug alone (P = .002).


CONCLUSIONS
Combined HDI and NF-kappaB inhibition using BAY-11-7085 sensitizes NSCLC cells to cell death and appears promising as a novel treatment strategy for this disease.
Department of Surgery, University of Virginia School of Medicine Charlottesville, VA 22908-0679, USA.
Brian K
BK
Rundall
Chadrick E
CE
Denlinger
David R
DR
Jones
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D010766:Phosphorylation; D013450:Sulfones; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat
D000890:Anti-Infective Agents; C416282:BAY 11-7085; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D051996:Transcription Factor RelA; D000077337:Vorinostat