title: The "survivin suppressants" NSC 80467 and YM155 induce a DNA damage response.
abstract: OBJECTIVE
  To establish whether NSC80467, a novel fused naphthquinone imidazolium, has a similar spectrum of activity to the well-characterized "survivin suppressant" YM155 and to extend mechanistic studies for this structural class of agent.
  
  
  METHODS
  NSC80467 and YM155 were analyzed in parallel using assays measuring viability, survivin suppression, inhibition of DNA/RNA/protein synthesis and the cellular response to DNA damage.
  
  
  RESULTS
  GI(50) values generated for both compounds in the NCI-60 screen yielded a correlation coefficient of 0.748, suggesting significant concordance. Both agents were also shown to inhibit protein expression of survivin [BIRC5]. COMPARE analysis identified DNA damaging agents chromomycin A3 and bisantrene HCl and one DNA-directed inhibitor of transcription, actinomycin D, as correlating with the activity of NSC80467 and YM155. Furthermore, both agents were shown to preferentially inhibit DNA, over RNA and protein synthesis. Thus, the ability of NSC80467 and YM155 to induce a DNA damage response was examined further. Treatment of PC3 cells with either agent resulted in dose-dependent induction of γH2AX and pKAP1, two markers of DNA damage. The concentrations of agent required to stimulate γH2AX were considerably lower than those required to inhibit survivin, implicating DNA damage as an initiating event. The DNA damage response was then confirmed in a panel of cell lines treated with NSC80467 or YM155, suggesting that γH2AX and pKAP1 have potential as response biomarkers.
  
  
  CONCLUSIONS
  These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression.
authors.affiliation: Biological Testing Branch, Developmental Therapeutics Program, Building 320, Room 9, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Glaros
authors.forename: Luke H
authors.initials: LH
authors.lastname: Stockwin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mullendore
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.forename: Bethanie L
authors.initials: BL
authors.lastname: Morrison
authors.forename: Dianne L
authors.initials: DL
authors.lastname: Newton
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020014:K562 Cells; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D000077022:Survivin; D013997:Time Factors; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; C575061:NSC80467; D009285:Naphthoquinones; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D000077022:Survivin; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; C523798:sepantronium