title: PARP inhibitor attenuated colony formation can be restored by MAP kinase inhibitors in different irradiated cancer cell lines.
abstract: Abstract Purpose: Sensitizing cancer cells to irradiation is a major challenge in clinical oncology. We aimed to define the signal transduction pathways involved in poly(ADP-ribose) polymerase (PARP) inhibitor-induced radiosensitization in various mammalian cancer lines.
  
  
  METHODS
  Clonogenic survival assays and Western blot examinations were performed following telecobalt irradiation of cancer cells in the presence or absence of various combinations of PARP- and selective mitogen-activated protein kinase (MAPK) inhibitors.
  
  
  RESULTS
  HO3089 resulted in significant cytotoxicity when combined with irradiation. In human U251 glioblastoma and A549 lung cancer cell lines, Erk1/2 and JNK/SAPK were found to mediate this effect of HO3089 since inhibitors of these kinases ameliorated it. In murine 4T1 breast cancer cell line, p38 MAPK rather than Erk1/2 or JNK/SAPK was identified as the main mediator of HO3089's radiosensitizing effect. Besides the aforementioned changes in kinase signaling, we detected increased p53, unchanged Bax and decreased Bcl-2 expression in the A549 cell line.
  
  
  CONCLUSIONS
  HO3089 sensitizes cancer cells to photon irradiation via proapoptotic processes where p53 plays a crucial role. Activation of MAPK pathways is regarded the consequence of irradiation-induced DNA damage, thus their inhibition can counteract the radiosenzitizing effect of the PARP inhibitor.
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs , Hungary.
authors.forename: Eniko
authors.initials: E
authors.lastname: Hocsak
authors.forename: Anna
authors.initials: A
authors.lastname: Cseh
authors.forename: Aliz
authors.initials: A
authors.lastname: Szabo
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Bellyei
authors.forename: Eva
authors.initials: E
authors.lastname: Pozsgai
authors.forename: Tamas
authors.initials: T
authors.lastname: Kalai
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Arpad
authors.initials: A
authors.lastname: Boronkai
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: D001562:Benzimidazoles; C508983:HO 3089; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases
keywords: PARP; clonogenic cell survival; p53; radiosensitizers