Induction Of Mitotic Abnormalities Research Articles

Polo-like kinase 1 inhibitor NMS-P937 represses nasopharyngeal carcinoma progression via induction of mitotic abnormalities.

Polo-like kinase 1 (PLK1) inhibitor NMS-P937 is a targeted therapeutic agent with good preclinical efficacy in various human cancers, and its therapeutic effect on nasopharyngeal carcinoma (NPC) remains to be determined. Here, to explore biological activity of NMS-P937 in NPC, multiple types of NPC cells were utilized. We tested IC50 values, carried out flow cytometry, western blot analysis analysis, immunofluorescence, and constructed subcutaneous xenograft mouse models. We found that treatment with NMS-P937 increased the proportion of G2/M phase NPC cells, where CyclinB1 expression was upregulated and CyclinE1 expression was downregulated. Besides, NMS-P937 treatment-induced NPC cell apoptosis with increased cleavage of PARP and caspase-3. Mechanistically, NMS-P937 treatment led to aberrant mitosis, causing increased reactive oxygen species (ROS) levels. ROS scavenger N-acetylcysteine partially reversed ROS levels induced by NMS-P937. Furthermore, NMS-P937 administration restrained NPC xenografts growth in nude mice. Overall, NMS-P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS-P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma.

Geospatial pattern of topsoil pollution and multi-endpoint toxicity in the petrochemical area of Augusta-Priolo (eastern Sicily, Italy)

The present study was aimed at identifying geospatial patterns of pollutants including concentrations and toxicity as complex environmental mixtures, in topsoil samples close to petrochemical facilities in the heavily industrialized area of Augusta and Priolo in south-eastern Sicily (Italy). Elemental analysis of soil was conducted by ICP-MS for 23 metals and 16 rare earth elements (REEs). Organic analyses were primarily focused on polycyclic aromatic hydrocarbons (PAHs) (16 parent homologs) and total aliphatic hydrocarbons (C10 – C40). Topsoil samples were tested for toxicity in multiple bioassay models including: 1) developmental defects and cytogenetic anomalies in sea urchin Sphaerechinus granularis early life stages; 2) growth inhibition of diatom Phaeodactylum tricornutum; 3) mortality in nematode Caenorhabditis elegans; and 4) induction of mitotic abnormalities in onion Allium cepa. Samples collected at sites closest to defined petrochemical facilities were highest in select pollutants and correlated with biological effects in different toxicity endpoints. A noteworthy finding was the increased level of total REEs in sites closest to petrochemical facilities, suggesting their contributions to identifying petrochemical sources of pollutants to the environment. The combined data obtained in the different bioassays allowed exploration of geospatial patterns of effect in biota as a function of contaminant levels. In conclusion, this study provides consistent data of soil toxicity, metal and REE contamination at Augusta-Priolo sampling sites, and may provide an appropriate baseline for epidemiological studies on high incidences of congenital birth defects in the area and identification of at-risk localities.

Abstract 3592: BaP induces chromosome missegregation through mitotic spindle defects in normal lung epithelial cells

Abstract Lung cancer remains the leading cause of cancer related deaths in the United States. Cancer results from an accumulation of multiple genetic events leading to genomic instability that is a crucial early event in carcinogenesis. Aneuploidy is the most frequently identified genomic abnormality in cancer. We have previously reported a significantly higher level of aneuploidy in smokers who developed lung cancer as compared to smoker controls. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is a pulmonary carcinogen and one of 60 different carcinogens found in tobacco smoke. In this study, we hypothesize that B(a)P disrupts mitotic spindle assembly that impairs the fidelity of mitosis leading to chromosome missegregation and aneuploidy. To test our hypothesis, we use confocal imaging in combination with traditional molecular biology techniques to dissect the precise mechanism by which B[a]P induces chromosome missegregation and aneuploidy. Mitotic spindle defects in the form of chromosome lags and bridges, monopolar and multipolar spindles, were assessed in normal lung epithelial cells after treatment with 10μM B[a]P for 6 hrs. Spindle defects were assessed at 24, 48, 72 and 96 hours after treatment. Immunofluorescence revealed abnormal mitosis in the prometaphase through the telophase stage of mitosis. Our result show that B[a]P exposure induced abnormal spindles in the form of monopolar (14%) and multipolar (4%) spindles. High resolution confocal images further revealed that B[a]P exposure led to misoriented mitotic spindles with an abnormal spindle angle [-380] relative to normal plane [180]. Chromosome lagging at both metaphase (17%) and anaphase (9%) has also been recorded in response to B[a]P exposure, observations that result from defects in the mitotic apparatus and kinetochores. Furthermore, we assessed the extent of B[a]P induced genetic instability [in the form of double strand DNA breaks] using gama-H2AX in order to elucidate the underlying mechanism associated with accumulated genetic damage and chromosome missegregation. Our data indicate that B[a]P results in accumulation of mitotic abnormalities and gama-H2AX foci (22%) peaks at 48 hr compared to other time points. Taken together, our data show that B[a]P potently induces mitotic abnormalities by disrupting kinetochore microtubules. The induction of mitotic abnormalities by B[a]P leading to chromosome missegregation and aneuploidy, would unravel a novel targetable molecular mechanism of cigarette smoke induced lung tumorigenesis. Citation Format: Jose T. Thaiparambil, Randa El-Zein. BaP induces chromosome missegregation through mitotic spindle defects in normal lung epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3592.

6DMAP inhibition of early cell cycle events and induction of mitotic abnormalities.

N-6 dimethylaminopurine (6DMAP) has been shown to induce aberrant mitosis in different cell types including Chinese hamster fibroblasts (CHEF/18). The mechanism of action and the cellular targets, however, are still not clear. We showed previously that in CHEF/18 cells this compound inhibits DNA synthesis with a kinetic of inhibition suggestive of an effect on early events of the cell cycle. In this paper we investigated which cellular targets were affected by 6DMAP and found that: (i) the compound inhibits phosphorylation of ribosomal protein S6 and activation of the 70 kDa S6 kinase (p70S6k) known to be activated by epidermal growth factor (EGF) in keeping with the notion that it is a protein kinase inhibitor; however the inhibition in vivo appears to be specific as MAP kinase phosphorylation is not inhibited; (ii) 6DMAP drastically affects cytoskeletal components leading to a rapid morphological change in most cells. These data, together with the findings that the dose range and the treatment time effective in inducing the micronuclei containing chromosomes were the same as for DNA synthesis inhibition, suggest that a disturbance in G1 of signal transduction pathways may contribute to abnormal mitosis.

Sublethal pH decrease may cause genetic damage to eukaryotic cell: A study on sea urchins and Salmonella typhimurium

Further evidence is reported here of genetic and developmental damage that can be induced by a sublethal pH decrease. The effects of three inorganic acids (HCl, H2SO4, and H3PO4) on embryos and sperm from the sea urchins Sphaerechinus granularis and Paracentrotus lividus were evaluated. In addition, acidification of the medium was tested for spontaneous reversion to His+ prototrophy in Salmonella typhimurium (strains TA97, TA98, TA100, TA102, TA1535) up to toxic levels, by both liquid incubation and agar plate incorporation. The induction of developmental and mitotic abnormalities in S. granularis confirmed our previous observations on P. lividus. Embryotoxicity was exerted in S. granularis more severely by H3PO4 than by HCl or H2SO4 (pH 7 to 6), while the induction of mitotic abnormalities appeared at a pH of less than or equal to 6.5 irrespective of the acids used. By suspending S. granularis or P. lividus sperm in acidified filtered seawater (fsw) and then inseminating the eggs in natural fsw (pH = 8.0), the offspring showed developmental and mitotic abnormalities. Low-pH-induced spermiotoxicity was ruled out in our experiments, since fertilization success of acid-exposed sperm was actually enhanced, as compared to sperm suspended in untreated fsw. The exposure of S. typhimurium to different pH's (ranging from 4 to 9) invariably failed to induce any changes in reversion rates, regardless of the acids (or alkali) being used. These results suggest that extracellular acidification may cause sublethal damage that in turn leads to an impairment of mitotic activity and cell differentiation.

Clastogenic effects of five naphto-nitro-furans: [formula omitted] induction of mitotic abnormalities : W. Venegas, Cl. Lasne and I. Chouroulinkov IRSC-CNRS - LRACC, B.P. No. 8, 94802 Villejuif Cédex, France

Clastogenic effects of five naphto-nitro-furans: [formula omitted] induction of mitotic abnormalities : W. Venegas, Cl. Lasne and I. Chouroulinkov IRSC-CNRS - LRACC, B.P. No. 8, 94802 Villejuif Cédex, France

Induction of Mitotic Abnormalities in Onion Root-Tips by Tobacco Smoke Condensate

Induction of Mitotic Abnormalities in Onion Root-Tips by Tobacco Smoke Condensate

Induction of mitotic abnormalities in the root tips ofAllium cepa by tobacco smoke

Es wurden Untersuchungen der Wirkung des Tabakrauches auf mitotische Fehler beiAllium-cepa-L.-Samlingen gemacht und dabei eine Abnahme des mitotischen Indexes und induzierte mitotische Missbilungen gefunden.

Induction of Mitotic Abnormalities in <i>Ornithogalum virens</i> by Tritiated Thymidine

Mitotic abnormalities in Ornithogalum virens Lindl. were studied by using tritiated thymidine as an internal mutagen. Two concentrations viz., 1.0μCi/ml and 2.0μCi, /ml tritiated thymidine were used in this investigation. The root tips were grown in the isotope solution for 4, 6 and 8 hours respectively and then they were transfered to isotope free nutrient solution for further growth of 6, 12, 18 and 24 hours respectively. Cells were scored at both metaphase and anaphases for various types of chromosomal aberrations. Chromatid and isochromatid breaks, chromatid intrachanges, severe chromosome fragmentation, chromosome rings, binucleate cells, single lagging chromosome at metaphase, tetraploid cells were the important types of aberrations observed. It was noticed that 2.0μCi/ml H3 thymidine concentration has caused a higher frequency of chromosomal aberrations than that of 1.0μCi/ml H3 thymidine concentration.

Induction of Mitotic Abnormalities in Certain Genera of Tribe Vicieae by Paradichlorobenzene

Effect of paradichlorobenzene on somatic chromosomes of Vicia faba, V. narbonensis, V. hirsuta, Pisum arvense and Lathyrus sativus was studied after giving a prolonged treatment. Various mitotic anomalies were encountered. These included shortening and thickening of chromosomes, precocious separation of chromatids, tetraploid cells, binucleate cells, chromosome bridges and chromosome breakage. The potentiality of PDB as a mutagenic substance had been emphasised and terms like PDB-treatment, PDB-mitosis and PDB-metaphase were suggested for convenient use. Chromosome breaks generally took place at the heterochromatic regions.