title: A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia.
abstract: The chemo- and radioresponse of tumor cells can be determined by genetic factors (e.g., those that modify cell cycle arrest, DNA damage repair or cell death) and microenvironmental factors, such as hypoxia. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that rapidly recognizes and binds to DNA breaks to facilitate DNA strand break repair. Pre-clinical data suggest that PARP inhibitors (PARPi) may potentiate the effects of radiotherapy and chemotherapy. However, it is unclear as to whether PARPi are effective against hypoxic cells. We therefore tested the role for a novel PARPi, ABT-888, as a radiosensitizing agent under hypoxic conditions. Using human prostate (DU-145, 22RV1) and non-small cell lung (H1299) cancer cell lines, we observed that ABT-888 inhibited both recombinant PARP activity and intracellular PARP activity (86% to 92% decrease in all 3 cells lines following 2.5 microM treatment). ABT-888 was toxic to both oxic and hypoxic cells. When ABT-888 was combined with ionizing radiation (IR), clonogenic radiation survival was decreased by 40-50% under oxic conditions. Under acute hypoxia, ABT-888 radiosensitized malignant cells to a level similar to oxic radiosensitivity. To our knowledge, this is the first study to demonstrate that inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of IR-PARPi has the potential to improve the therapeutic ratio of radiotherapy.
authors.affiliation: Department of Radiation Oncology, University of Toronto, Ont., Canada.
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Liu
authors.forename: Carla
authors.initials: C
authors.lastname: Coackley
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.forename: Farid
authors.initials: F
authors.lastname: Jalali
authors.forename: Norman
authors.initials: N
authors.lastname: Chan
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D011838:Radiation-Sensitizing Agents; C521013:veliparib