Reduction In Radiosensitivity Research Articles

The mir-199b-5p encapsulated in adipocyte-derived exosomes mediates radioresistance of colorectal cancer cells by targeting JAG1

Radiotherapy is a key treatment option for colorectal cancer, but its efficacy varies among patients. Our previous studies suggested that adipose tissue may confer the radioresistance of several abdominal tumors, such as pancreatic cancer, biliary cancer, and others. In the present work, the effects of adipocytes in regulating the radiosensitivity of colorectal cancer are explored for the first time. It was found that colony formation was increased and radiation-induced apoptosis decreased in colorectal cancer cells HCT8 and HCT116 co-cultured with adipocytes, which verified the mediation of adipocyte-driven radioresistance in colorectal cancer in vitro. Next, the colorectal cancer cells were incubated with adipocyte-derived exosomes, and a perceptible reduction in radiosensitivity was detected. Furthermore, to investigate the possible mechanisms involved, the exosomes were isolated, the encapsulated microRNAs were extracted and analyzed by small RNA sequencing. Based on bioinformatics analysis and qRT-PCR verification, miR-199b-5p was chosen for functional annotation. It was shown that miR-199b-5p expression was significantly upregulated after 6 Gy irradiation, and overexpressed miR-199b-5p significantly suppressed the radiosensitivity of HCT8 and HCT116 cells. In addition, jagged canonical Notch ligand 1(JAG1) was identified as the target gene of miR-199b-5p by using bioinformatics prediction and dual luciferase reporter gene assay. It was demonstrated that JAG1 conferred the radioresistance of colorectal cancer cells both in vivo and in vitro. Taken together, the present study demonstrates that adipocytes trigger the radioresistance of colorectal cancer cells, probably by targeting JAG1 through an adipocyte-derived exosomal miR-199b-5p.

Study of the impact of CLPTM1L on radiosensitivity of lung cancer

Objective To study the correlation of cleft lip and palate transmembrane 1 like (CLPTM1L) expression and radiosensitivity of lung cancer cells. Methods Thiazolyl blue tetrazolium bromide (MTT) and cell colony formation assays were used to determine cell growth and survival. Western Blot assay was employed to measure protein expression. Results The results demonstrated a negative correlation between the CLPTM1L expression level and radiosensitivity of lung cancer cells. A lower radiosensitivity in lung cancer cells containing high level of CLPTM1L expression, and vice versa. Enforced expression of CLPTM1L resulted in a significant reduction of radiosensitivity in lung cancer cells irradiated with γ-rays. On the contrary, a marked elevation of radiosensitivity was observed in lung cancer cells transfected with CLPTM1L siRNA. Conclusions CLPTM1L may be a novel target gene in mediating radiosensitivity of lung cancer cells. Key words: Cleft lip and palate transmembrane 1 like; Radiation tolerance; Lung neoplasms; γ-rays

Age-dependent changes in oxygen tension, radiation dose and sensitivity within normal and diseased coronary arteries–Part C: Oxygen effect and its implications on high- and low-LET dose

Purpose: The aim is to study the implications of the decrease in oxygen concentration in the coronary artery walls with age and atherosclerosis, particularly with regard to an associated reduction in the radiosensitivity to high-and low-linear-energy-transfer (LET) irradiation.Materials and methods: In accompanying papers, the age-dependent morphology and composition for the wall layers of normal and diseased coronary arteries were developed in Part A from published data. In Part B, the oxygen concentration in the coronary artery walls was evaluated taking account the diffusion of oxygen from blood and the solubility of oxygen in tissues. In this part the oxygen effect was evaluated using published experimental data.Results: Based on simulation results from the one-dimensional diffusion model, the oxygen enhancement ratio (OER) is lower in the hypoxic vessel walls of aged and atherosclerotic arteries. Consequently the high-LET radiation damage arising from both the radon (222Rn) and thoron (220Rn) decay chains to the intimal layer of highly diseased arteries was estimated to be reduced by ∼37% due to hypoxia. A greater reduction in radiosensitivity (51%) due to hypoxia was determined for low-LET irradiation.Conclusion: These results imply that the oxygen effect, and other radiation biological factors, have a significant influence on radiation biological effects and risk of cardiovascular disease (CVD) to Japanese atomic bomb (A-bomb) survivors and patients receiving radiotherapy of the mediastinum.

Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice

Purpose The effect of recombinant human erythropoietin (rhEPO) on the radiosensitivity of human tumor xenografts growing in anemic and nonanemic nude mice was studied. Methods and materials Anemia was induced by total body irradiation ([TBI], 2 × 4 Gy) of mice before tumor implantation into the subcutis of the hind leg. The development of anemia was prevented by rhEPO (750 U/kg s.c.) given 3 times weekly starting 2 weeks before TBI. Fourteen days after fractionated TBI (tumor volume of approx. 40 mm 3), single-dose irradiation of the tumor with varying doses was performed so that in full dose–response relationship for the probability of tumor cure was obtained. Results Radiation-induced anemia (hemoglobin concentration [cHb] = 9.9 g/dl) led to a reduced radiosensitivity compared to controls [49.4 vs. 40.1 Gy radiation dose to control 50% of the tumors (TCD50)]. Upon rhEPO treatment for anemia prevention (cHb = 13.3 g/dl), the TCD50 was 39.8 Gy, illustrating restored radiosensitivity compared to anemic mice. Conclusion These data provide further experimental evidence for restored radiosensitivity upon prevention of anemia with rhEPO.

Induction of radioresistance to accelerated carbon-ion beams in recipient cells by nitric oxide excreted from irradiated donor cells of human glioblastoma

Purpose : To investigate whether nitric oxide excreted from cells irradiated with accelerated carbon-ion beams modulates cellular radiosensitivity against irradiation in human glioblastoma A-172 and T98G cells. Materials and methods : Western-blot analysis of inducible nitric oxide synthase, hsp72 and p53, the concentration assay of nitrite in medium and cell survival assay after irradiation with accelerated carbon-ion beams were performed. Results : The accumulation of inducible nitric oxide synthase was caused by accelerated carbon-ion beam irradiation of T98G cells but not of A-172 cells. The accumulation of hsp72 and p53 was observed in A-172 cells after exposure to the conditioned medium of the T98G cells irradiated with accelerated carbon-ion beams, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase to the medium. The radiosensitivity of A-172 cells was reduced in the conditioned medium of the T98G cells irradiated with accelerated carbonion beams compared with conventional fresh growth medium, and the reduction of radiosensitivity was abolished by the addition of an inducible nitric oxide synthase inhibitor to the conditioned medium. Conclusions : Nitric oxide excreted from the irradiated donor cells with accelerated carbon-ion beams could modulate the radiosensitivity of recipient cells. These findings indicate the importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to accelerated heavy ions.

Isolation of radiosensitive and radioresistant mutants from a medulloblastoma cell line.

Two mutant clones, one radiosensitive (OS-3) and one resistant (OR-5), were isolated from ONS-76 after screening 2400 clones by the replica micro-well technique. These two clones exhibited significantly different radiosensitivity, with D37 values of 4.7Gy in OR-5 and 1.7Gy in OS-3. After gamma irradiation (8Gy), OR-5 exhibited greater G2 arrest than sensitive clone OS-3. Administration of 5mM of caffeine resulted in greater cell killing in OR-5 than in OS-3, with an almost complete release of G2 block. These observations support the notion that the G2 block contributes to the repair process of DNA damage after irradiation. The present results suggest that clones with a large postirradiation G2 block may show a greater reduction in radiosensitivity if the G2 block is released artificially. The study of the mutant clones described herein may provide important clues to the mechanism by which glioma cells acquire radioresistance.

Long-Term Repair in Vivo of Colony-Forming Ability and Chromosomal Injury in X-Irradiated Mouse Hepatocytes

The radiosensitivity of mouse hepatocytes in vivo was measured in terms of clonogenicity or chromosome damage (micronucleus production). Within 24 h of irradiation there was a dose-dependent increase in clonogenicity (dose-modifying factor, DMF = 1.37 +/- 0.09) followed by long-term repair which resulted in a DMF of 3.49 +/- 0.23 at 11 months. Such repair also took place, but to a lesser extent, after the end of fractionated irradiation. Cell proliferation, measured by tritiated thymidine autoradiography, was insufficient to explain the long-term reduction in radiosensitivity in terms of a dose-dependent replacement of damaged cells. Although there was a reduction in the frequency of cells with micronuclei, postirradiation, the magnitude of this decrease was relatively small; the DMF for micronucleus-free cells at 11 months was only 1.49 +/- 0.25. Thus the long-term increase in clonogenicity can only partially be explained in terms of repair of chromosome injury, assessed by the production of micronuclei.

Effect of Radiation on the Regulation of Sodium-Dependent Glucose Transport in LLC-PK 1 Epithelial Cell Line: Possible Model for Gene Expression

Low concentrations of glucose induce cultured kidney epithelial cells (LLC-PK1) to produce hexose transport proteins. We have investigated the effects of ionizing radiation on this induction process in plateau-phase cultures. The induced production of hexose transporters, requiring approximately 6 to 9 days for complete expression, can be inhibited by irradiation during the first 4 days. After the fourth postinduction day, radiation sensitivity decreases with almost no radiation effect on the induction of hexose transport apparent by the sixth day of the induction period. The D0 value associated with the induction block is approximately 25 Gy, a value which is considerably greater than that necessary to inhibit cell replication. Hexose transport, itself resistant to ionizing radiation at doses in excess of 100 Gy, is sensitive to cycloheximide throughout the induction period. The sensitivity to cycloheximide decreases during the last 2 days of the induction period, approximately 1 day after the reduction in radiosensitivity. Based on these properties hexose transport may be a convenient model for the study of radiation effects upon gene expression in this cell line.

Effect of heavy water on radiosensitivity of maize and barley seeds

Damage as a result of irradiation by sparsely ionizing radiation of maize and barley seeds is lower when dry seeds are soaked in D 2O than in H 2O prior to irradiation. The reduction in radiosensitivity by D 2O was mainly manifested in the presence of oxygen there being no effect of D 2O when seeds were irradiated anaerobically. Evidently, the reduction in radiation damage due to D 2O is largely oxygen-dependent.

NUCLEAR VOLUME, NUCLEAR DNA CONTENT AND RADIOSENSITIVITY IN BRASSICA AND ALLIED GENERA

Relationships between nuclear volume, nuclear DNA content and radiosensitivity were studied on genera of a family, species of a genus, and strains a species. Throughout the materials observed the radiosensitivity was more markedly correlated with the mean DNA content per chromosome than with the estimated interphase chromosome volume. Data involved information about an appreciable reduction in nuclear DNA cdntent in cultivated polyploid plants associated with a proportional reduction in radiosensitivity.

EFFECT OF PROGRESSIVE CHANGES IN BODY TEMPERATURE OF RATS ON TISSUE OXYGEN-TENSIONS, IN RELATION TO RADIOSENSITIVITY.

SummaryOxygen-tensions, measured polarographically in tissues of rats subjected to progressive hypothermia and hyperthermia, are reported. Corresponding radiosensitivity values have been estimated and indicate that both hypothermia (15°c) and hyperthermia (41°c) cause radioprotection due to ‘oxygen effect’, with a reduction in radiosensitivity of haemopoietic tissues to ∼ 75 per cent and ∼ 85 per cent of maximum values respectively. The physiological reasons for these findings are discussed.

The rejoining time of chromatid breaks induced by gamma radiation in Vicia faba root tips at 3degrees C.

The observation was made previously that the reduction in radiosensitivity in Vicia faba (as measured by postirradiation root growth) by prolonging the exposure time from about 10 minutes to 24 hours is much less marked at 3 degrees C. than at 19 degrees C. If chromosome damage is mainly responsible for the reduced root growth, this observation might be explained by a smaller drop in the "two-hit" aberration component, resulting from an increased time for which breaks are available for rejoining at 3 degrees C. This hypothesis was tested by comparing chromatid aberration frequencies in root meristem cells produced by 105 rads of (60)Co gamma rays, given at dose rates of 19.4 and 0.073 rads per minute. Beans were maintained in aerated water at 2 degrees C. prior to and during irradiation, and at this temperature the rate of development of cells was such that the two different exposure times both occupied a period during which the cell sensitivity was approximately constant. Immediately subsequent to irradiation, the roots were returned to 19 degrees C. and examined cytologically. All chromatid aberrations were less frequent after low dose rate treatment, but only the chromatid interchange reduction was significant. The average time for which breaks are available for reunion, calculated from Lea's G function, was found to be 12 hours (95 per cent C.L. 6 to 24 hours).

Effect of Nitrogen and Hydrogen Gas under Pressure on the Radiosensitivity of the Broad Bean Root

In the course of experiments on the modification of the sensitivity of bean roots to X-rays by hydrogen gas, control groups of roots were irradiated in nitrogen at a pressure of 50 atm. We found that pressure alone, either of hydrogen or nitrogen, had only a slight effect, if any, on the growth of the roots. As already reported (1, 2), we observed that the presence of 50 atm of H2 during irradiation markedly reduced radiosensitivity. An additional and unexpected finding, which appeared in two separate experiments, was a reduction in radiosensitivity due to 50 atm of nitrogen, which, in the presence of 1 atm of air, appeared to be an even better protector than hydrogen under pressure. Personal communications from L. H. Gray and John Read reveal that each of these investigators has observed a reduced radiosensitivity under nitrogen pressure (at 50 atm and 14 atm, respectively), although in neither case was it wholly consistent. We have now carried out experiments which confirm beyond doubt that, in the presence of 1 atm of air, nitrogen at pressures of 21 atm or more has a protective action which is equivalent to the complete removal of oxygen.