title: Inhibition of the checkpoint kinase Chk1 induces DNA damage and cell death in human Leukemia and Lymphoma cells.
abstract: BACKGROUND
  Chk1 forms a core component of the DNA damage response and small molecule inhibitors are currently being investigated in the clinic as cytotoxic chemotherapy potentiators. Recent evidence suggests that Chk1 inhibitors may demonstrate significant single agent activity in tumors with specific DNA repair defects, a constitutively activated DNA damage response or oncogene induced replicative stress.
  
  
  METHODS
  Growth inhibition induced by the small molecule Chk1 inhibitor V158411 was assessed in a panel of human leukemia and lymphoma cell lines and compared to cancer cell lines derived from solid tumors. The effects on cell cycle and DNA damage response markers were further evaluated.
  
  
  RESULTS
  Leukemia and lymphoma cell lines were identified as particularly sensitive to the Chk1 inhibitor V158411 (mean GI50 0.17 μM) compared to colon (2.8 μM) or lung (6.9 μM) cancer cell lines. Chk1 inhibition by V158411 in the leukemia and lymphoma cell lines induced DNA fragmentation and cell death that was both caspase dependent and independent, and prevented cells undergoing mitosis. An analysis of in vitro pharmacodynamic markers identified a dose dependent decrease in Chk1 and cyclin B1 protein levels and Cdc2 Thr15 phosphorylation along with a concomitant increase in H2AX phosphorylation at Ser139 following V158411 treatment.
  
  
  CONCLUSIONS
  These data support the further evaluation of Chk1 inhibitors in hematopoietic cancers as single agents as well as in combination with standard of care cytotoxic drugs.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bryant
authors.forename: Kirsten
authors.initials: K
authors.lastname: Scriven
authors.affiliation: Vernalis R&D Ltd, Granta Park, Cambridge CB21 6GB, UK. a.massey@vernalis.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D002455:Cell Division; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008938:Mitosis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C000596547:V158411; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1