DNA repair inhibition

Hartwig A. 1998. Carcinogenicity of metal compounds possible role of DNA repair inhibition. 

Mouse fibroblasts DNA repair inhibition NH4CI NT + Capuco 1977... 

An important determinant of whether or not a cell becomes initiated by a chemical carcinogen is DNA repair. Inhibition of the excision repair system allows a greater chance that the carcinogenic damage will not be repaired, thus leading to the irreversible initiated carcinogenic state (1). Likewise, inhibition or induction of error prone DNA repair could lead to a drastic modification of the carcinogenesis process (1). 

Inhibition or induction of DNA repair Inhibition or enhancement of cellular proliferation ... 

Haetwig a (1994) Role of DNA repair inhibition in lead and cadmium-induced genotoxicity a review. Environ Health Perspect 102, Suppl 3 45-50. 

Veuger SJ, Curtin NJ, Richardson CJ et aL Radiosensitizaiion and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) poty-merase-1. Cancer Res 2003 63 6008-6015. 

It seems certain that the effect of SAB on the cytotoxicity and DNA repair of cells treated with monofunctional alkylating agents is mediated via an inhibition of ADP-ribosyl transferase activity (7, 8). Nevertheless, the pleiotropic effects of SAB could result in the modulation of the cytotoxicity of other dmgs independent of ADP-ribosyl transferase inhibition. In this paper, we describe the cytotoxic effects of SAB on a range of purine base and nucleoside analogues. The data lead us to hypothesize that SAB modulates purine analogue cytotoxicity by mechanism(s) independent of DNA repair inhibition, but involving effects on de novo purine biosynthesis and nucleoside transport. 

While direct interactions of cadmium ions with DNA appear to be of little importance, interactions with proteins are of high significance. Especially the DNA repair inhibitions but also altered cell proliferation and/or diminished cell cycle control have frequently been observed at low, non-cytotoxic concentrations of cadmium, raising the question of particularly sensitive targets of cadmium ions. Relevant mechanisms include elevated levels of ROS, interactions with homeostasis and cellular functions of essential metal ions like zinc, calcium, and iron and the interference with cellular redox regulation. 

Mitomycin C was found to have broad activity against a range of tumors and has been used clinically since the early 1960s [14, 15]. It causes many specific cellular effects, including inhibition of DNA synthesis, recombination, chromosome breakage, sister chromatid exchange, induction of DNA repair, and induction of... 

Nitro PAHs have been shown to exhibit a large variety of biological activities. Included in these are the induction of mutations in bacterial (Table I) and eukaryotic cells (9,17,54-57), the neoplastic transformation of cultured mammalian cells (58-59), and the induction of DNA strand breaks (60), DNA repair (61-62), sister chromatid exchanges (63-64), and chromosomal aberrations (65-66). Nitro PAHs have also been demonstrated to bind cellular DNA in bacteria (67-73) and mammalian cells (74-77), to inhibit preferentially the growth of repair-deficient bacteria (78), to have recombinogenic activity in yeast (66,79-80) and to induce tumors in experimental animals (Table II). 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

Numerous studies were dedicated to the effects of flavonoids on microsomal and mitochondrial lipid peroxidation. Kaempferol, quercetin, 7,8-dihydroxyflavone and D-catechin inhibited lipid peroxidation of light mitochondrial fraction from the rat liver initiated by the xanthine oxidase system [126]. Catechin, rutin, and naringin inhibited microsomal lipid peroxidation, xanthine oxidase activity, and DNA cleavage [127]. Myricetin inhibited ferric nitrilotriacetate-induced DNA oxidation and lipid peroxidation in primary rat hepatocyte cultures and activated DNA repair process [128]. 

Several inorganic arsenic compounds are weak inducers of chromosomal aberrations, sister chromatid exchange, and in vitro transformation of mammalian and piscine cells. However, there is no conclusive evidence that arsenic causes point mutations in any cellular system (Pershagen and Valuer 1979 Belton et al. 1985 Lee et al. 1985 Deknudt et al. 1986 Manna and Mukheijee 1989). Studies with bacteria suggest that arsenite is a comutagen, or may inhibit DNA repair (Belton et al. 1985). 

Low concentrations (10 /iM or less) of mercury have little effect on cellular viability and stimulate RNA and DNA synthesis, whereas higher concentrations are cytotoxic and inhibit DNA, RNA and protein synthesis [145, 146, 246-248 ]. Mercuric chloride is able to selectively block CHO (Chinese hamster ovary) cells in S phase, which is related to the chemical reactivity and uptake into the cells [249], The cytotoxicity of mercury(II) compounds is probably related to their ability to inhibit DNA polymerase a activity and inhibit not only DNA synthesis but also DNA repair [250, 251]. 

Although cadmium is not strongly mutagenic, it is known that it causes increased oxidative DNA damage and that it inhibits the DNA repair systems. It has also been found to induce cell death both by necrosis and apoptosis. Since the latter is extremely calcium-dependent, it seems likely that the pro-apoptotic effects of cadmium are due to its interference with calcium homeostasis. 

Poirier MC, DeCicco BT, Lieberman MW. 1975. Nonspecific inhibition of DNA repair synthesis by tumor promotors in human diploid fibroblasts damage with N-acetoxy-2-acetylaminofluorene. Cancer Res 35 1392-1397. 

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