Modulation of Mitomycin C-induced Genotoxicity by Acetyl- and Thio- Analogues of Salicylic Acid (original) (raw)
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Antigenotoxic effect of lipoic acid against mitomycin-C in human lymphocyte cultures
Antitumor agents are used in therapy against many forms of human cancer. One of these is mitomycin-C (MMC). As with many agents, it can interact with biological molecules and can induce genetic hazards in non-tumor cells. One of the possible approaches to protect DNA from this damage is to supply antioxidants that can remove free radicals produced by antitumor agents. Lipoic acid (LA) is known as one of the most powerful antioxidants. The aim of this study was to investigate antigenotoxic effects of LA against MMC induced chromosomal aberrations (CA), sister chromatid exchanges (SCE) and micronu-cleus (MN) formation in human lymphocytes. Lym-phocytes were treated with 0.2 lg MMC/heparinized mL for 48 h. Three different concentrations (0.5, 1, 2 lg/mL) of LA were used together with MMC in three different applications; 1 h pre-treatment, simultaneous treatment and 1 h post-treatment. A negative, a positive and a solvent control were also included. In all the cultures treated with MMC ? LA, the frequency of abnormal cells and CA/cell significantly decreased compared to MMC. Statistically significant reduction was also observed in SCE/cell and MN frequencies in all treatments. These results demonstrated anticlastogenic and antimutagenic effects of LA against MMC induced genotoxicity. LA showed the most efficient effect during 1 h pretreatment. On the other hand, MMC ? LA treatments induced significant reduction in mitotic index than that of MMC treatment alone. These results are encouraging that LA can be a possible chemopre-ventive agent in tumorigenesis in both cancer patients and in health care persons handling anti-cancer drugs.
Toxicology and Industrial Health, 2012
4-Thujanol (sabinene hydrate), a bicyclic monoterpene alcohol, is found in the essential oils of many aromatic and medicinal plants and is widely used as a fragrance and flavouring agent in many different products. The aim of this study was to evaluate the protective effects of 4-thujanol against the genotoxic effects induced by mitomycin C (MMC) and cyclophosphamide (CP) in human lymphocytes, using the chromosome aberrations, sister chromatid exchanges, and micronucleus tests, in the absence and in the presence of S9 mix, respectively. The cells were treated with 0.25 mg/mL MMC and 28 mg/mL CP as alone and cotreated with 13 þ 0.25, 26 þ 0.25, and 52 þ 0.25 mg/mL 4-thujanol þ MMC and with 13 þ 28, 26 þ 28, and 52 þ 28 mg/mL 4-thujanol þ CP as a mixture. The present study showed that 4-thujanol was unable to reduce the genetic damage induced by MMC, in the absence of S9 mix. On the other hand, probably the metabolites of 4-thujanol act as an antagonist and markedly antagonize CP-induced genotoxicity, in the presence of S9 mix. In general, 4-thujanol þ MMC and 4-thujanol þ CP decreased the mitotic index, proliferation index and nuclear division index to the same extent or more than those of individual exposure of MMC or CP. In conclusion, 4-thujanol significantly reduced (p < 0.001) the genotoxic damage induced by CP but not MMC when compared with the respective positive control alone. We can suggest that 4-thujanol may improve the chemopreventive effects and may also reduce the harmful side effects of CP, which is widely used in chemotherapy against cancer, without reducing its antiproliferative activities.
Asian Pacific Journal of Cancer Prevention, 2012
Vanillic acid, a vegetable phenolic compound, is a strong antioxidant. The aim of the present study was to determine its effects on mitomycin C-induced DNA damage in human blood lymphocyte cultures in vitro, both alone and in combination with mitomycin C (MMC). The cytokinesis block micronucleus test and alkaline comet assay were used to determine genotoxic damage and anti-genotoxic effects of vanillic acid at the DNA and chromosome levels. MMC induced genotoxicity at a dose of 0.25 µg/ml. Vanillic acid (1 µg/ml) significantly reduced both the rates of DNA damaged cells and the frequency of micronucleated cells. A high dose of vanillic acid (2 µg/ml) itself had genotoxic effects on DNA. In addition, both test systems showed similar results when tested with the negative control, consisting of dimethyl sulfoxide (DMSO) in combination with vanillic acid (1 µg/ml)+MMC. In conclusion, vanillic acid could prevent oxidative damage to DNA and chromosomes when used at an appropriately low dose.
Mutation Research, 2015
In Mexico, as in many other countries, traditional medicine is used for the treatment of several diseases. In particular, Amphipterygium adstringens infusion is used for gastritis, gastric ulcers, and gastric cancer. Extracts from this tree have microbicidal effects against Helicobacter pylori, an important risk factor for gastric cancer development. Anacardic acids are constituents of A. adstringens, and 6-pentadecyl salicylic acid (6-PSA) is the most abundant. However, there is a lack of information regarding the effects of 6-PSA on cancer cells. Therefore, we investigated whether 6-PSA has differential effects on the induction of genotoxicity, cytostaticity, and apoptosis in normal human peripheral blood mononucleated cells (PBMCs), bone marrow polychromatic erythrocytes of Balb/c mice, and human transformed cell lines derived from both gastric cancer (AGS cells) and leukaemia (K562 cells). Treatment with 6-PSA (30-150 M) reduced the viability of AGS and K562 cells together with a moderate, but significant, increase in the frequency of micronucleated cells and the induction of DNA breakage (Comet Assay). Moreover, 6-PSA increased the apoptosis rate in both the AGS and K562 cell lines in a caspase 8-dependent manner. In contrast, neither cytotoxicity nor genotoxicity were observed in PBMCs or bone marrow polychromatic erythrocytes of Balb/c mice after treatment with low doses of 6-PSA (0.2-2.0 mg/Kg). Instead, 6-PSA treatment resulted in the inhibition of PBMC proliferation, which was reversible after the compound was removed. Additionally, 6-PSA treatments (2-20 mg/Kg) increased the frequency of mature polychromatic erythrocytes in the bone marrow, suggesting a possible effect on the differentiation process of immune cells. The present results indicate that 6-PSA induces cytotoxicity and moderate genotoxicity, together with an increase in the apoptosis rate, in a caspase 8-dependent manner in gastric cancer cells. In contrast, a low toxicity was observed when PBMCs were exposed to 6-PSA.
Arhiv za higijenu rada i toksikologiju, 2004
Although chemotherapy targets cancer tissue, it also damages the DNA of non-cancer cells. The aim of this study was to evaluate the in vitro genotoxic potential of therapeutic concentrations of bleomycin and mitomycin C, added alone or in combination to cultures of human peripheral lymphocytes. The levels of DNA damage and repair were assessed using the alkaline comet assay immediately after cell treatment as well as 24 and 48 hours following treatment. The results indicate that individual drugs and their combination induce a significant DNA damage to peripheral blood lymphocytes. Bleomycin alone induced the highest levels of primary DNA damage immediately after cell treatment. Although mitomycin C alone induced massive cross-linking and retarded DNA migration in resting cells, active proliferation and repair processes significantly increased DNA damage. Combined, they showed a synergetic effect, inducing complex patterns of DNA damage in peripheral blood lymphocytes and producing d...
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2011
The cytogenetic damage inflicted by the synthetic pyrethroid insecticide cypermethrin (CYP) on the bonemarrow of male white rats, as well as possible protective role of two natural elements: garlic extract (GRE, 500 mg/kg) and vitamin C (VTC, 20 mg/kg) against the mutagenic potential of the insecticide were assessed. CYP was orally intubated in a single treatment (1/2 LD 50 ) or in repeated treatments (1/5 LD 50 daily, for 5 successive days), either alone, or concomitantly with repeated oral intubations (5 successive days) of each individual putative protector, or with their combination (GRE or/and VTC). One hundred and twenty male rats were divided over into five groups of each 24 animals. The groups received nothing, a single dose or repeated treatments with insecticide alone, or associated with putative natural elements, separately or in combinations. Animals were sacrificed at their scheduled times and their femoral bonemarrows were flushed out to be utilized in the micronucleus test and metaphase chromosomal aberration assay. The results show that CYP administration significantly induced clastogenic effects, as revealed by the significant increase in the mean frequencies of micronucleated polychromatic erythrocytes and various structural chromosomal aberrations in bone-marrow metaphase cells of all groups of treated rats. On the other hand, this investigation clearly revealed the protective role of GRE and VTC, either each alone or in combination, against the mutagenic potential of cypermethrin: the garlic extract was often more efficient in its protective action against the insecticide toxicity than vitamin C. while the combination of both natural elements produced, in most cases, a more pronounced protective effect than when each was administered alone.
PLOS ONE, 2015
Chalcones present several biological activities and sulfonamide chalcone derivatives have shown important biological applications, including antitumor activity. In this study, genotoxic, cytotoxic, antigenotoxic, and anticytotoxic activities of the sulfonamide chalcone N-{4-[3-(4-nitrophenyl)prop-2-enoyl]phenyl} benzenesulfonamide (CPN) were assessed using the Salmonella typhimurium reverse mutation test (Ames test) and the mouse bone marrow micronucleus test. The results showed that CPN caused a small increase in the number of histidine revertant colonies in S. typhimurium strains TA98 and TA100, but not statistically significant (p > 0.05). The antimutagenicity test showed that CPN significantly decreased the number of His + revertants in strain TA98 at all doses tested (p < 0.05), whereas in strain TA100 this occurred only at doses higher than 50 μg/plate (p < 0.05). The results of the micronucleus test indicated that CPN significantly increased the frequency of micronucleated polychromatic erythrocytes (MNPCE) at 24 h and 48 h, revealing a genotoxic effect of this compound. Also, a significant decrease in polychromatic/normochromatic erythrocyte ratio (PCE/NCE) was observed at the higher doses of CPN at 24 h and 48 h (p < 0.05), indicating its cytotoxic action. CPN co-administered with mitomycin C (MMC) significantly decreased the frequency of MNPCE at almost all doses tested at 24 h (p < 0.05), showing its antigenotoxic activity, and also presented a small decrease in MNPCE at 48 h (p > 0.05). Additionally, CPN co-administered with MMC significantly increased PCE/NCE ratio at all doses tested, demonstrating its anticytotoxic effect. In summary, CPN presented genotoxic, cytotoxic, antigenotoxic, and anticytotoxic properties.
Mitomycin C-induced damage and repair in human and pig lymphocytes
Mutation research, 1986
Human and pig lymphocytes were used to compare the chromosomal sensitivity to MMC and the efficiency of repair of MMC-induced DNA adducts. No significant interspecies differences were found. The results obtained show that SCE frequencies are linearly correlated with MMC doses. During the G0 period there are indications that lymphocytes may half-repair the DNA-interstrand crosslinks transforming bi- into mono-adducts. SCEs induced by MMC decrease to near control levels in the second cell cycle. Therefore, most MMC lesions responsible for SCEs should be repaired between the moment in the first S phase in which they induce the exchanges and the onset of the second S period.