ArticleInternational journal of radiation oncology, biology, physics2016
Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality.
Article in International journal of radiation oncology, biology, physics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 44 citations in OpenAlex.
- Tirapazamine sensitises hypoxic homologous recombination-proficient NSCLC to PARP inhibition.Cell death discovery · 2026Article
- Impact of the ATM/Chk2 pathway and cell cycle phase on radiation-induced senescence in A549 human lung cancer cells.Biomedical reports · 2025Article
- PARP inhibitors as radiosensitizers: a comprehensive review of preclinical evidence and clinical applications.Frontiers in oncology · 2025Review
- Cancer stem cells and their niche in cancer progression and therapy.Cancer cell international · 2023Review
- PARP inhibitors combined with radiotherapy: are we ready?Frontiers in pharmacology · 2023Review
- Polyadenosine diphosphate-ribose polymerase inhibitors: advances, implications, and challenges in tumor radiotherapy sensitization.Frontiers in oncology · 2023Review
- Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies.Journal of enzyme inhibition and medicinal chemistry · 2022Review
- Novel Implications of Nanoparticle-Enhanced Radiotherapy and Brachytherapy: Z-Effect and Tumor Hypoxia.Metabolites · 2022Review
- Review
- DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models.Molecular cancer therapeutics · 2021Article
- Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model.British journal of cancer · 2021Article
- Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy.Frontiers in oncology · 2021Review
- Differential therapeutic effects of PARP and ATR inhibition combined with radiotherapy in the treatment of subcutaneous versus orthotopic lung tumour models.British journal of cancer · 2020Article
- Organoids as ComplexCellular and molecular bioengineering · 2020Review
- Article
- NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and "osmotic reprogramming" in colorectal cancer.Cell death & disease · 2020Article
- PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation.Journal of radiation research · 2020Article
- Radical esophagectomy for stage II and III thoracic esophageal squamous cell carcinoma followed by adjuvant radiotherapy with or without chemotherapy: Which is more beneficial?Thoracic cancer · 2020Article
- Fluzoparib increases radiation sensitivity of non-small cell lung cancer (NSCLC) cells without BRCA1/2 mutation, a novel PARP1 inhibitor undergoing clinical trials.Journal of cancer research and clinical oncology · 2020Article
- Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.The Journal of clinical investigation · 2020Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
purposePoly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiation therapy in preclinical models of human non-small cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models. METHODS AND MATERIALS: NSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth.
resultsIn vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors.
conclusionsOur data suggest that hypoxia potentiates the radiation-sensitizing effects of olaparib by contextual synthetic killing, and that tumor hypoxia may be a potential biomarker for selecting patients who may get the greatest benefit from the addition of olaparib to radiation therapy.
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