粒子線によるDNA損傷の修復メカニズム

筑波大学 (University of Tsukuba)201

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cell

Immunomodulatory Effects of Hypocrellin A on MHC-restricted Antigen Processing

Hypocrellin A has gained much attention in recent years due to its light-induced antitumor, antifungal and antiviral activities. Here we report that hypocrellin A exerts immunomodulatory effects on MHC-restricted presentation of antigen. Hypocrellin A inhibited class II-MHC restricted presentation of exogenous antigen, but not class I MHC-restricted presentation of exogenous antigen, in dendritic cells. Hypocrellin A also inhibited the cytosolic pathway of endogenous antigen presentation. However, hypocrellin A did not inhibit the expression of class I and class II MHC molecules on dendritic cells (DCs), the phagocytic activity of DCs, or the H-2Kb-restricted presentation of a synthetic peptide, SIINFEKL. These results show that hypocrellin A differentially modulates the MHC-restricted antigen presentation pathways

The abscopal effect induced by in situ-irradiated peripheral tumor cells in a murine GL261 brain tumor model

Background: Localized radiotherapy is considered to act as an adjuvant for systemic anti-tumor immunity. We examined whether in situ-irradiated peripheral tumor cells can evoke an abscopal effect in the brain inhibiting malignant tumor growth.Methods: Syngeneic albino C57BL/6 mice were inoculated with mouse glioma cells (GL261) transfected with the Kusabira Orange fluorescent gene (GL261-mKO) for monitoring the tumor growth with in vivo imaging system. GL261-mKO cells were subcutaneously implanted in the thigh and irradiated by X-rays (20 Gy) for in situ vaccination. Ex vivo-irradiated GL261-mKO cells were used as a conventional whole-cell vaccine for comparison. Following these treatments, the brain was challenged with the same GL261-mKO cells, and survival analyses were performed by Kaplan-Meier analysis. In addition, IFN-γ release from splenocytes and CD8+ cells infiltration into the brain were analyzed.Results: Both in situ- and ex vivo-irradiated vaccines significantly prolonged the survival of the mice compared to the control group bearing an intracerebral tumor. Although there was no significant difference in survival between the two vaccination methods, in situ-vaccinated mice with local control by irradiation completely rejected the implanted tumor cells in the brain. In contrast, mice with local failure demonstrated a rapid growth of both subcutaneous and challenged intracerebral tumors. The cured mice demonstrated an accumulation of CD8+ cells surrounding the inoculation site, as well as increased release of IFN-γ via an ELISPOT assay.Conclusions: Our results indicate that the X-ray irradiation to peripheral tumors evoked a protective, tumor-specific immune response in the brain when the peripheral tumors were successfully cured by irradiation

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells