Selective vulnerability of ARID1A deficient colon cancer cells to combined radiation and ATR-inhibitor therapy.

ARID1A is frequently mutated in colorectal cancer (CRC) cells. Loss of ARID1A function compromises DNA damage repair and increases the reliance of tumor cells on ATR-dependent DNA repair pathways. Here, we investigated the effect of ionizing radiation (IR), in combination with ATR inhibitors (ATRi) in CRC cell lines with proficient and deficient ARID1A.

DNA-dependent protein kinase: effect on DSB repair, G2/M checkpoint and mode of cell death in NSCLC cell lines.

To evaluate the effect of NU7026, a specific inhibitor of DNA-PKcs, on DNA-double strand break (DSB) repair in a cell cycle specific manner, on the G2/M checkpoint, mitotic progression, apoptosis and clonogenic survival in non-small-cell lung carcinoma (NSCLC) cell lines with different p53 status. Cell cycle progression, and hyperploidy were evaluated using flow cytometry. Polynucleation as a measure for mitotic catastrophe (MC) was evaluated by fluorescence microscopy.

Metformin enhances the radiosensitizing effect of cisplatin in non-small cell lung cancer cell lines with different cisplatin sensitivities.

Cisplatin is an extensively used chemotherapeutic drug for lung cancer, but the development of resistance decreases its effectiveness in the treatments of non-small cell lung cancer (NSCLC). In this study, we examined the effects of metformin, a widely used antidiabetic drug, on cisplatin radiosensitization in NSCLC cell lines. Human NSCLC cell lines, A549 (cisplatin-resistant) and H460 (cisplatin-sensitive), were treated with metformin, cisplatin or a combination of both drugs before ionizing radiation.

Targeting of BRM Sensitizes -Mutant Lung Cancer Cell Lines to Radiotherapy.

Targeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here, we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically non-small cell lung carcinoma (NSCLC) cells with mutations in the other subunit BRG1/SMARCA4 toward ionizing radiation (IR). Knockdown of BRM with siRNA or shRNA and its consequences for radiation sensitivity as measured by clonogenic survival and plaque-monolayer control was studied in different NSCLC lines with or without mutations and in primary fibroblasts.

Epigenetic silencing and activation of transcription: influence on the radiation sensitivity of glioma cell lines.

Purpose: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively, on the radioresponsiveness of glioma cell lines.

Materials And Methods: Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated.

Dependence of radiation-induced H2AX phosphorylation on histone methylation: evidence from the chromatin immunoprecipitation assay.

Purpose: To evaluate ionizing radiation (IR)-induced DNA damage response within euchromatic and heterochromatic regions.

Material And Methods: Chromatin immunoprecipitation (ChIP) and immunofluorescence analysis were used to explore the distribution of phosphorylated H2AX (γH2AX).

Results: ChlP experiments after IR at 30 and 60 Gy showed by a factor of 1.

Inhibiting the aurora B kinase potently suppresses repopulation during fractionated irradiation of human lung cancer cell lines.

Purpose: The use of molecular-targeted agents during radiotherapy of non-small-cell lung cancer (NSCLC) is a promising strategy to inhibit repopulation, thereby improving therapeutic outcome. We assessed the combined effectiveness of inhibiting Aurora B kinase and irradiation on human NSCLC cell lines in vitro.

Methods And Materials: NSCLC cell lines were exposed to concentrations of AZD1152-hydroxyquinazoline pyrazol anilide (AZD1152-HQPA) inhibiting colony formation by 50% (IC50(clone)) in combination with single dose irradiation or different fractionation schedules using multiple 2-Gy fractions per day up to total doses of 4-40 Gy.

Long-term in vivo effects of cisplatin on gamma-H2AX foci signaling in peripheral lymphocytes of tumor patients after irradiation.

Purpose: This study determined the effects of cis-diamminedichloroplatinum(II) on radiation-induced foci formation of gamma-H2AX and Rad51 in lymphocytes.

Experimental Design: Twenty-eight cancer patients were irradiated for intrathoracic, pelvic, or head and neck tumors and received simultaneous cisplatin containing chemotherapy. The effect of cisplatin on radiation-induced gamma-H2AX and Rad51 foci as a response to ionizing radiation-induced DNA double-strand breaks was measured in lymphocytes after in vivo and in vitro radiochemotherapy.

gamma-H2AX foci formation in peripheral blood lymphocytes of tumor patients after local radiotherapy to different sites of the body: dependence on the dose-distribution, irradiated site and time from start of treatment.

Purpose: To evaluate the relationship between an estimated integral total body radiation dose delivered and phosphorylated histone H2AX protein (gamma-H2AX) foci formation in peripheral blood lymphocytes of cancer patients.

Material And Methods: gamma-H2AX formation was quantified as the mean number of foci per lymphocyte (N(meanH2AX)) and the percentage of lymphocytes with > or =n foci. The integrated total body radiation dose was estimated from the dose volume histogram of patient's body corrected for the proportion of the body scanned by computed tomography for 3D treatment planning.