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DNA Damaging Agents (dna + damaging_agent)
Selected AbstractsAscochlorin activates p53 in a manner distinct from DNA damaging agentsINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Ji-Hak Jeong Abstract Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins. © 2009 UICC [source] Influence of glutathione S-transferase pi and p53 expression on tumor frequency and spectrum in miceINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Laurent Gate Abstract The role of glutathione S-transferase , (GST,) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GST, has been identified as a modulator of cell signaling by interacting with and inhibiting c-Jun N-terminal kinase (JNK). This kinase has been in turn described as a regulator of p53 stability and transcriptional activity. To study the possible interaction between GST, and p53, we crossed GST,-deficient animals with p53,/, mice. Double knock out animals were viable but developed tumors within 6 months of age; the life span of these animals was however similar to that of GST,+/,/p53,/, and GST,+/+/p53,/,. Mice heterozygous for p53 lived significantly longer than the p53,/, animals and developed tumors much later, and the expression of GST, did not significantly modify the life span of the animals. In contrast, in a wild-type p53 background, GST,,/, mice developed tumors with a significantly higher frequency than heterozygous and wild-type animals with a median tumor free life span 20 weeks shorter. In addition, in p53+/+ background, one third of the GST,,/, animals developed lung adenomas, while less than 10% of GST,+/, and GST,+/+ presented such tumors. GST, expression did not alter the expression of tumorigenesis markers such as COX-2 or ornithine decarboxylase in response to phorbol ester. Furthermore, GST,-deficient mouse embryo fibroblasts were more sensitive to H2O2 -induced apoptosis. P53,/, cells, independent of GST, status, were more sensitive to UV and other DNA damaging agents than their wild-type counterparts. These results suggest that GST, may play a protective role in the development of spontaneous tumors. [source] Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acidJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2004Douglas C. Marchion Abstract Acetylation of histones leads to conformational changes of DNA. We have previously shown that the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induced cell cycle arrest, differentiation, and apoptosis. In addition to their antitumor effects as single agents, HDAC inhibitors may cause conformational changes in the chromatin, rendering the DNA more vulnerable to DNA damaging agents. We examined the effects of SAHA on cell death induced by topo II inhibitors in breast cancer cell lines. Topo II inhibitors stabilize the topo II,DNA complex, resulting in DNA damage. Treatment of cells with SAHA promoted chromatin decondensation associated with increased nuclear concentration and DNA binding of the topo II inhibitor and subsequent potentiation of DNA damage. While SAHA-induced histone hyperacetylation occurred as early as 4 h, chromatin decondensation was most profound at 48 h. SAHA-induced potentiation of topo II inhibitors was sequence-specific. Pre-exposure of cells to SAHA for 48 h was synergistic, whereas shorter pre-exposure periods abrogated synergy and exposure of cells to SAHA after the topo II inhibitor resulted in antagonistic effects. Synergy was not observed in cells with depleted topo II levels. These effects were not limited to specific types of topo II inhibitors. We propose that SAHA significantly potentiates the DNA damage induced by topo II inhibitors; however, synergy is dependent on the sequence of drug administration and the expression of the target. These findings may impact the clinical development of combining HDAC inhibitors with DNA damaging agents. © 2004 Wiley-Liss, Inc. [source] Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiationMOLECULAR CARCINOGENESIS, Issue 8 2008Beate Köberle Abstract Most testicular germ cell tumors are curable using cisplatin-based chemotherapy, and cell lines from these tumors are unusually sensitive to cisplatin and other DNA-damaging agents. It has been suggested that this might be caused by a lower-than normal nucleotide excision repair (NER) activity. Previous studies found that cell lines from testicular germ cell tumors have on average about one-third the level of the NER protein XPA in comparison to cell lines from other tumors. We asked whether over-expression of XPA protein would alleviate the cellular sensitivity and increase the DNA repair capacity of a testis tumor cell line. Increasing XPA levels in 833K cells by 10-fold did not increase resistance to UV irradiation. XPA was localized to the cell nucleus in all cell lines, before and after exposure to UV-radiation. 833K cells were proficient in removing UV radiation-induced photoproducts from the genome and increased XPA did not enhance the rate of removal. Further, over-expressing functional XPA protein did not correlate with increased resistance of 833K testis tumor cells to cisplatin. Thus, although the amount of XPA in this testis tumor cell line is lower than normal, it is sufficient for NER in vivo. The relative sensitivity of testis tumor cells to cisplatin, UV radiation, and other DNA damaging agents is likely related not to NER capacity, but to other factors such as the integrity of the p53 pathway in these cells. © 2008 Wiley-Liss, Inc. [source] Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cellTHE JOURNAL OF GENE MEDICINE, Issue 1 2009Yunfeng Li Abstract Background The extremely poor prognosis of patients with pancreatic ductal adenocarcinoma indicates the need for novel therapeutic approaches. The growth arrest and DNA damage-inducible (Gadd) gene Gadd45a is a member of a group of genes that are induced by DNA damaging agents and growth arrest signals. Methods We evaluated the biological activity of Gadd45a in pancreatic ductal adenocarcinoma cancer-derived cell lines and assessed the efficacy of a combined treatment with adenoviral-mediated expression of Gadd45a (Ad-G45a) and anticancer drug (Etoposide, cisplatin, 5-fluorouracil, respectively) for the PANC1 cell line. Results Gadd45a is variously expressed in cell lines derived from pancreatic ductal adenocarcinoma cancer and adenoviral-mediated expression of Gadd45a (Ad-G45a) in these cells results in apoptosis via caspase activation and cell-cycle arrest in the G2/M phase. Gadd45a significantly increased the chemosensitivity of PANC1, which may be due to abundant apoptosis induction and cell cycle arrest. By combinational treatment of Ad-G45a infection and chemotherapeutics, Gadd45a expression was elevated to a higher extent in cancer cells with wild-type p53 than in that with knocked-out p53 status, indicating a higher chemosensitivity to cancer chemotherapy. Conclusions Gadd45a may be a promising candidate for use in cancer gene therapy in combination with chemotherapeutic agents. Copyright © 2008 John Wiley & Sons, Ltd. [source] G2 -phase radiation response in lymphoblastoid cell lines from Nijmegen breakage syndromeCELL PROLIFERATION, Issue 2 2002A. Antoccia The relationship between G2 -phase checkpoint activation, cytoplasmic cyclin-B1 accumulation and nuclear phosphorylation of p34CDC2 was studied in Nijmegen breakage syndrome cells treated with DNA damaging agents. Experiments were performed on lymphoblastoid cell lines from four Nijmegen breakage syndrome patients with different mutations, as well as on cells from an ataxia telangiectasia patient. Lymphoblastoid cell lines were irradiated with 0.50,2 Gy X-rays and the percentage of G2 -phase accumulated cells was evaluated by means of flow cytometry in samples that were harvested 24 h later. The G2 -checkpoint activation was analysed by scoring the mitotic index at 2 and 4 h after treatment with 0.5 and 1 Gy X-rays and treatment with the DNA double-strand break inducer calicheamicin-,1. Cytoplasmic accumulation of cyclin-B1 was evaluated by means of fluorescence immunostaining or Western blotting, in cells harvested shortly after irradiation with 1 and 2 Gy. The extent of tyrosine 15-phosphorylated p34CDC2 was assessed in the nuclear fractions. Nijmegen breakage syndrome cells showed suboptimal G2 -phase checkpoint activation respect to normal cells and were greatly different from ataxia telangiectasia cells. Increased cytoplasmic cyclin-B1 accumulation was detected by both immunofluorescence and immunoblot in normal as well as in Nijmegen breakage syndrome cells. Furthermore, nuclear p34CDC2. phosphorylation was detected at a higher level in Nijmegen breakage syndrome than in ataxia telangiectasia cells. In conclusion, our data do not suggest that failure to activate checkpoints plays a major role in the radiosensitivity of Nijmegen breakage syndrome cells. [source] | |||||||||||||