Search results for "Cell killing"
showing 10 items of 30 documents
APE/Ref-1 and the mammalian response to genotoxic stress.
2003
Human apurinic/apyrimidinic endonuclease/redox factor-1 (hAPE/Ref-1) is a multifunctional protein involved in the repair of DNA damaged by oxidative or alkylating compounds as well as in the regulation of stress inducible transcription factors such as AP-1, NF-kappaB, HIF-1 and p53. With respect to transcriptional regulation, both redox dependent and independent mechanisms have been described. APE/Ref-1 also acts as a transcriptional repressor. Recent data indicate that APE/Ref-1 negatively regulates the activity of the Ras-related GTPase Rac1. How these different physiological activities of APE/Ref-1 are coordinated is poorly understood. So far, convincing evidence is available that the ex…
Mechanisms and consequences of methylating agent-induced SCEs and chromosomal aberrations: a long road traveled and still a far way to go.
2003
Since the milestone work of Evans and Scott, demonstrating the replication dependence of alkylation-induced aberrations, and Obe and Natarajan, pointing to the critical role of DNA double-strand breaks (DSBs) as the ultimate trigger of aberrations, the field has grown extensively. A notable example is the identification of DNA methylation lesions provoking chromosome breakage (clastogenic) effects, which made it possible to model clastogenic pathways evoked by genotoxins. Experiments with repair-deficient mutants and transgenic cell lines revealed both O<sup>6</sup>-methylguanine (O<sup>6</sup>MeG) and N- methylpurines as critical lesions. For S<sub>N</sub&g…
Ultraviolet light-induced apoptotic death is impaired by the HMG-CoA reductase inhibitor lovastatin.
2003
HMG-CoA reductase inhibitors (i.e., statins) attenuate C-terminal isoprenylation of Rho GTPases, thereby inhibiting UV-C-induced activation of c-Jun-N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs). Inhibition of UV-C-triggered JNK/SAPK activation by lovastatin is due to inhibition of Rac-SEK1/MKK4-mediated phosphorylation of JNKs/SAPKs at Thr183/Tyr185. UV-C-stimulated phosphorylation of p38 kinase (Thr180/Tyr182) is also impaired by lovastatin. Cell killing provoked by UV-C irradiation was significantly inhibited by lovastatin. This was paralleled by a reduced frequency of chromosomal aberrations, accelerated recovery from UV-C-induced transient replication blockage, inhib…
Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells
2012
MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage an…
Comparison of the genotoxic and apoptosis-inducing properties of ganciclovir and penciclovir in Chinese hamster ovary cells transfected with the thym…
2000
We studied the genotoxic and apoptosis-inducing properties of ganciclovir (GCV) and penciclovir (PCV) using Chinese hamster ovary cells stably transfected with the thymidine kinase (tk) gene of herpes simplex virus-1 (HSV-1). Cells expressing HSVtk were 300 and 100 times more sensitive than their isogenic HSVtk- counterparts to the cytotoxic effects of GCV and PCV, respectively. Using radiolabeled drugs, GCV was found to be incorporated into the genomic DNA much more effectively than PCV. GCV was highly potent in inducing chromosomal aberrations compared with PCV, which provoked less sister chromatid exchanges and chromosomal changes using equimolar or equitoxic doses. For both agents, apop…
Porphyrin-bile acid conjugates: from saccharide recognition in the solution to the selective cancer cell fluorescence detection.
2008
This paper describes the preparation and use of conjugates of porphyrins and bile acids as ligands to bind to tumor expressed saccharides. Bile acid-porphyrin conjugates were tested for recognition of saccharides that are typically present on malignant tumor cells. Fluorescence microscopy, in vitro PDT cell killing, and PDT of subcutaneous 4T1 mouse tumors is reported. High selectivity for saccharide cancer markers and cancer cells was observed. This in vivo and in vitro study demonstrated high potential use for these compounds in targeted photodynamic therapy.
Interferon-γ inhibits replication of subgenomic and genomic hepatitis C virus RNAs
2002
Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-alpha) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-alpha on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show th…
Apoptosis induced by (E)-5-(2-bromovinyl)-2'-deoxyuridine in varicella zoster virus thymidine kinase-expressing cells is driven by activation of c-Ju…
2003
The molecular mode of cell killing by the antiviral drug (E)-5-(2-bromovinyl-2'-deoxyuridine (BVDU) was studied in Chinese hamster ovary (CHO) cells stably transfected with the thymidine kinase gene (tk) of varicella zoster virus (CHO-VZVtk). The colony-forming ability of the cells was reduced to <1% at a concentration of approximately 1 microM BVDU, whereas for nontransfected cells or cells transfected with tk gene of herpes simplex virus type 1 (CHO-HSVtk), a 1000-fold higher dose was required to achieve the same response. BVDU inhibited thymidylate synthase in CHO-VZVtk but not in CHO-HSVtk and control cells. On the other hand, the drug was incorporated into DNA of VZVtk- and HSVtk-expre…
Physiological Effects of Hyperthermia
1987
Hyperthermia as a modality for the treatment of malignant tumors, either alone or in combination with radiation or anticancer drugs, is rapidly becoming a clinical reality. Three different mechanisms of action have provided the rationale for considering the use of hyperthermia as an antitumor agent. At moderate hyperthermia (T=40˚ -42.5˚ C), heat can increase cell killing in a synergistic way following exposure of a tumor to ionizing radiation. This radiosensitization is probably based on, among other things, the inhibited repair of radiation-induced DNA lesions. Elevated tissue temperatures at 40˚ -42.5˚ C also sensitize tumor cells to certain chemotherapeutic drugs, particularly to alkyla…
Impact of Localized Microwave Hyperthermia on the Oxygenation Status of Malignant Tumors
1982
Considerable insight into the mechanisms of heat induced cell death in vitro has been gained during recent years (for reviews see 1–3). Besides the direct cell killing effect of heat, many microenvironmental or milieu factors seem to play an important role during heat treatment of solid tumors in vivo, such that a preferential effect of hyperthermia on tumors has been postulated for the in situ conditions. Environmental factors affecting the tumor milieu, such as tissue oxygen partial pressures, pH values, glucose (?) and lactate levels, nutrient supply and drainage of wastes, have thus become a subject of topical interest.