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A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia.
- Source :
-
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Radiother Oncol] 2008 Aug; Vol. 88 (2), pp. 258-68. Date of Electronic Publication: 2008 May 02. - Publication Year :
- 2008
-
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.
- Subjects :
- Analysis of Variance
Apoptosis
Blotting, Western
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung radiotherapy
Cell Line, Tumor
Fluorescent Antibody Technique, Indirect
Humans
Hypoxia
Lung Neoplasms drug therapy
Lung Neoplasms radiotherapy
Male
Benzimidazoles pharmacology
Carcinoma, Non-Small-Cell Lung therapy
DNA Repair drug effects
Lung Neoplasms therapy
Prostatic Neoplasms drug therapy
Radiation-Sensitizing Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0167-8140
- Volume :
- 88
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 18456354
- Full Text :
- https://doi.org/10.1016/j.radonc.2008.04.005