1. PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation
- Author
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Du Junyan, Tetsuo Akimoto, Hidehiro Hojo, Shun-ichiro Kageyama, Masaki Nakamura, Atsushi Motegi, and Katsuya Tsuchihara
- Subjects
Radiation-Sensitizing Agents ,DNA Repair ,Cell Survival ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,BRCA ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,PARP ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Regular Paper ,Carcinoma ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,esophageal cancer ,Clonogenic assay ,Tumor Stem Cell Assay ,030304 developmental biology ,Photons ,0303 health sciences ,Chemotherapy ,Radiation ,Combination chemotherapy ,Esophageal cancer ,medicine.disease ,Gene Expression Regulation, Neoplastic ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,Cancer research ,Phthalazines ,Dose Fractionation, Radiation ,Esophageal Squamous Cell Carcinoma ,Protons ,Cell survival curve ,proton ,DNA Damage - Abstract
Proton beam therapy (PBT) combined with chemotherapy, such as cis-diamminedichloroplatinum (II) (CDDP) and 5-fluorouracil (5-FU), has been employed as an alternative approach to improve clinical outcomes. PBT has been reported to be effective against esophageal cancer. However, apart from 5-FU and CDDP, almost no other drug has been tested in combined chemotherapy with PBT. Therefore, we investigated the effects of a poly (ADP-ribose) polymerase inhibitor on enhancing proton beam effects using esophageal cancer cell lines that exhibit resistance to radiation and CDDP. Esophageal squamous cell carcinoma cell lines OE-21 and KYSE-450 were exposed to the drugs for 1 h prior to irradiation. The cell survival curve was obtained using a clonogenic assay and the sensitizing effect ratio (SER) was calculated. The clonogenic assay was used to compare the effect of multi-fractioned irradiation between 8 Gy/1 fraction (fr) and 8 Gy/4 fr. γH2AX, Rad51, BRCA1, BRCA2 and 53BP1 foci were detected via immunofluorescence. Olaparib exhibited an SER of 1.5–1.7 on PBT. The same sensitizing effect was exhibited in multi-fractioned irradiation, and the combined use increased the expression of double-strand breaks and homologous recombination-related genes in an additive manner. Such additive effects were not observed on non-homologous end joining-related genes. We demonstrated that olaparib has a high sensitizing effect on PBT in platinum- and radiation-resistant esophageal cancer cells. Our results suggest a potential clinical application of olaparib-proton irradiation (PT) against platinum- and radiation-resistant esophageal cancer.
- Published
- 2020
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