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PubMed1986

Post-treatments with sodium arsenite during G2 enhance the frequency of chromosomal aberrations induced by S-dependent clastogens.

Treatment with sodium arsenite during the G2 phase potentiated the chromatid breaks and chromatid exchanges induced by ultraviolet light or 4-nitroquinoline 1-oxide but not those induced by methyl methanesulfonate, ethyl methanesulfonate, mitomycin C or cisplatin in Chinese hamster ovary cells. A comparison was made between the effects of treatment during G2 with sodium arsenite, cytosine-beta-D-arabinofuranoside, aphidicolin, hydroxyurea, caffeine, 3-aminobenzamide and novobiocin on the frequency of chromosomal aberrations induced by the above-mentioned S-dependent clastogens. It was found that the effects varied considerably, both quantitatively and qualitatively. However, potentiation was more often observed in the chromosomal aberrations induced by ultraviolet light and 4-nitroquinoline 1-oxide than by other S-dependent clastogens, and the frequency of chromatid exchanges was potentiated only in cells pretreated with ultraviolet light or 4-nitroquinoline 1-oxide. Furthermore, for all of the S-dependent clastogens studied, treatment with cytosine-beta-D-arabinofuranoside during the G2 phase potentiated the frequency of chromatid breaks but not the frequency of chromatid exchanges.

Animals↗
PubMed2006

Radiosensitization of tumor cells by modulation of ATM kinase.

PURPOSE: To elucidate the relationship between the radiation-induced activation of ataxia telangiectasia mutated (ATM) kinase, G2 arrest and the caffeine-induced radiosensitization. METHOD: RKO cells (human colorectal cancer cells) and ATM kinase over-expressing RKO/ATM cells were used. The cellular radiosensitivity was determined with clonogenic survival assay and the cell cycle progression, including G2 arrest, was studied with flow cytometry. The activity of ATM kinase, check point 2 (Chk2) kinase and cycline B1/cell division cycle 2 (Cdc2) kinase was investigated. The radiosensitivity of RKO xenografts grown in nude mice was studied. RESULTS: RKO/ATM cells were radioresistant as compared with RKO cells. There was a greater increase in ATM kinase activity and G2 arrest in RKO/ATM cells than in RKO cells. Caffeine also sensitized both RKO cells and RKO/ATM cells to radiation. The caffeine treatment suppressed the radiation-induced activation of ATM kinase, suppressed the activation of Chk2 kinase and inhibited the accumulation of cells in G2 phase. The activity of cycline B1/Cdc2 kinase increased earlier but decayed rapidly in the presence of caffeine. Caffeine enhanced radiation-induced growth delay of RKO xenografts. CONCLUSIONS: Caffeine inhibited the radiation-induced activation of ATM kinase, thereby preventing the accumulation of cells in G2 phase. Consequently, radiosensitivity of cells increased in the presence of caffeine both in vitro and in vivo.

Apoptosis↗
PubMed1985

Concentration-dependent effects of foscarnet on the cell cycle.

The mechanism of toxicity of foscarnet was studied by monitoring its effects on the cell cycle of exponentially growing, semisynchronous human embryo cells in culture. The effects of foscarnet on the cell cycle were dependent on the concentration of drug used. At 1 mM, cell division was reduced by 50%, whereas the cell flow was mainly reduced in the G2 phase of the cell cycle, leading to an increase in the proportion of G2+M cells. The minor reduction of thymidine incorporation in S phase cells provided additional evidence that 1 mM foscarnet did not specifically inhibit DNA synthesis. Cell division was greatly reduced at 2.5 mM foscarnet, and the G2 phase was markedly affected, whereas S cell flow was less reduced. S cell flow was 10% per h and thymidine incorporation was 25% that of control cells, while a block in the G2+M phase was evident. On the other hand, at a concentration of 5 mM foscarnet, the cell flow was greatly reduced in the G1 and S phases, with less reduction of G2 cell flow and cells accumulated in the S phase. The effects of foscarnet on the cell cycle were more pronounced with increasing times up to 72 h, which could not be explained by the slow penetration of foscarnet which required only 4 to 8 h to achieve constant levels. At 2.5 and 5 mM foscarnet, there was the additional effect of the cell membranes becoming more leaky as a result of foscarnet toxicity which might contribute to the toxic effects of the drug at high concentrations. When foscarnet was removed from the medium, the effects on the cell cycle were rapidly reversed, in the time needed for foscarnet to diffuse out from the cells, which indicates the reversible nature of the toxic effects of foscarnet.

Antiviral Agents↗
PubMed1987

Effects of repair inhibition in the G1 phase of clastogen-treated human lymphocytes on the frequencies of chromosome-type and chromatid-type aberrations and sister-chromatid exchanges.

It has been shown that certain types of DNA lesions induced by an S-dependent clastogen are converted to chromosome-type aberrations when their repair is inhibited in the G1 phase of the cell cycle. The purpose of the present study was to investigate which kinds of repair inhibitors have the ability to induce chromosome-type aberrations in cells having DNA lesions and which kinds of DNA lesions will be converted to chromosome-type aberrations when their repair is inhibited. For this purpose, human peripheral blood lymphocytes, which were treated with a clastogen in their G0 phase, were post-treated with one of several kinds of repair inhibitors in the G1 phase, and resulting frequencies of both chromosome-type and chromatid-type aberrations as well as of sister-chromatid exchanges (SCEs) were compared with those of the control cultures: chromatid-type aberrations and SCEs were adopted as cytogenetic indicators of lesions remaining in S and G2 phases. Chemicals used for the induction of DNA lesions were 4-nitroquinoline 1-oxide (4NQO), methyl methanesulfonate (MMS) and mitomycin C (MMC); inhibitors used were excess thymidine (dThd), caffeine, hydroxyurea (HU), 5-fluoro-2'-deoxyuridine (FdUrd), 1-beta-D-arabinofuranosylcytosine (ara C), 9-beta-D-arabinofuranosyladenine (ara A), 1-beta-D-arabinofuranosylthymine (ara T) and aphidicolin (APC). Induction of chromosome-type aberrations was observed in cells pretreated with 4NQO or MMS followed by ara C, ara A, ara T or APC, whereas other combinations of a clastogen and an inhibitor did not induce them. Among the inhibitors, ara C alone induced chromosome-type aberrations in cells without pretreatment. Chromatid-type aberrations were increased only in cells pretreated with MMC and their frequency was enhanced further by post-treatment with ara C. All of the clastogens used in the present experiments induced SCEs. Most inhibitors did not modify the SCE frequencies except for ara C which synergistically increased the frequency in MMC-treated cells. The present study offers further evidence that the lesions responsible for chromosome-type aberrations are those which are repaired quickly, and that they are converted to chromosome-type aberrations when repair by polymerase alpha is inhibited. The effects of ara C on MMC-induced lesions are considered residual effects of ara C treatment in the S or G2 phases rather than repair inhibition in the G1 phase.

Cell Cycle↗
PubMed1986

Changes in nuclear and nucleolar protein content during the growth and differentiation of root parenchyma cells in plant species with different DNA-endoreplication dynamics.

Using cytophotometric procedures, we measured the nuclear and nucleolar protein content of successive zones of growth and differentiation in consecutive (1-7 mm) root segments obtained from eight species of the Angiospermae after staining the preparations with Feulgen-Naphthol Yellow S (F-NYS). In meristematic cells the nuclear and nucleolar protein content was found to double during the cell cycle. In species in which differentiation occurs at the same time as nuclear DNA endoreplication, i.e. Vicia faba subsp. minor, V. faba subsp. major, Pisum sativum, Hordeum vulgare and Amaryllis belladonna, the pool of nuclear proteins observed during the G2 phase of the cell cycle was seen in the differentiated zone in nuclei containing 8C DNA. Species in which differentiation is not accompanied by the process of nuclear DNA endoreplication, i.e. Levisticum officinale, Tulipa kaufmanniana and Haemanthus katharinae, exhibited the highest nuclear proteins content during the G2 phase of the cell cycle; comparably high values were not found in the differentiated zone. A decrease in nucleolar protein content was observed during the process of differentiation, this tendency being more evident in the studied species that do not exhibit endoreplication.

Animals↗
PubMed1982

Replication and recovery of nuclear DNA in UV-irradiated eggs of Lymnaea stagnalis (mollusca, gastropoda).

Synchronized and oriented egg cells of L. stagnalis have been irradiated with UV light during the G2 phase of the 2nd cleavage cycle; next the egg cells were treated with caffeine (3 X 10(-3)M) for varying periods during the 2nd and the 3rd cleavage cycle. In a second experiment the egg cells were irradiated at the same stage in the G2-phase with different UV doses, and then treated with caffeine until the beginning of the 3rd cleavage. In the caffeine-treated egg cells the two cleavage cycles following irradiation appeared to be lengthened, whereas in non-caffeine controls only the first cleavage cycle after irradiation is longer. It is concluded that the extension of the 3rd cleavage cycle is to be attributed to a prolongation of the S phase, which is not caused by an inhibition by caffeine of the initiation of the DNA synthesis. The results point to an effect of caffeine on the post-replication mode of repair; lesions in the DNA are not rendered innocuous in the presence of caffeine. At the beginning of the next cleavage cycle these lesions still have an inhibiting effect on the progression of DNA synthesis. Morphogenesis was reduced by increasing UV doses; with caffeine less than 7% of the embryos developed normally. These results may indicate an error-prone repair mechanism.

Animals↗
PubMed1992

High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-beta.

We investigated the effects of glucose concentration in serum-free media on the proliferative growth response of a cultured murine mesangial cell line. Raising the ambient D-glucose concentration from 100 mg/dl to 450 mg/dl stimulated cell proliferation after 24 to 48 hours but had a growth inhibitory effect after 72 to 96 hours of incubation. This biphasic proliferative response to high glucose concentration was not mediated by the elevated osmolarity of the medium and did not occur when L-glucose was used. The early phase of glucose-induced proliferation was associated with increased expression of the immediate early genes c-myc and egr-1 as well as with induction of the S-phase related proliferating nuclear cell antigen (PCNA). Several lines of evidence indicated that the late phase of glucose-induced growth inhibition was mediated by the bioactivation of endogenous transforming growth factor beta (TGF-beta). Neutralizing antibody against TGF-beta prevented the late inhibitory effects of glucose on proliferation. On the other hand, exogenous TGF-beta (1 ng/ml) significantly inhibited basal proliferation in mesangial cells. Furthermore, Northern blot analysis revealed that TGF-beta 1 mRNA was induced by 450 mg/dl glucose in the medium after 48 to 72 hours, but not after 24 hours. Cell cycle analysis demonstrated that mesangial cells incubated in high glucose for 24 hours have a higher percentage of cells in the S-G2 phase of the cell cycle compared with cells grown in normal glucose concentration. After 48 hours of culture in elevated glucose concentration, the percentage of cells in S-G2 phase was decreased, and became comparable to that of cells in normal glucose concentration. However, the addition of neutralizing anti-TGF-beta antibody stimulated the progression of cells towards S-G2 in high glucose medium after 48 hours. The findings of this study demonstrate a biphasic growth response of mesangial cells when they were cultured in high glucose concentration; initially there was a transient stimulation of replication for 24 to 48 hours followed by a sustained inhibition after longer incubation periods. This inhibition may be mediated by the glucose-induced synthesis and/or bioactivation of TGF-beta which can inhibit proliferation of mesangial cells in an autocrine fashion.

Animals↗
PubMed1992

Cytostatic activity of new synthetic anti-tumor aza-alkyllysophospholipids.

Alkyllysophospholipids are analogues of the naturally occurring 2-lysophosphatidylcholine which have been reported to have selective in vitro/in vivo anti-tumor activity. Their antiproliferative effect has been found against a variety of animal and human tumor cell lines. We have characterized the cytostatic activity of 2 newly synthetized aza-alkyllysophospholipids (AALPs), the BN52205 and the BN52211, on a human tumor cell line derived from a colon adenocarcinoma, the HT29. We used 3 different flow cytometric approaches to study which phase of the cell cycle was the most sensitive to the antiproliferative activity of the 2 AALPs. By applying the biparametric analysis of 5'-bromo-2-deoxyuridine incorporation vs. DNA content we have been able to demonstrate that the 2 AALPs do not interfere with the S phase of the cell cycle. The simultaneous measurement of total nuclear protein vs. DNA content in isolated HT29 nuclei enabled us to exclude a block in the M phase of the cell cycle. Finally, stathmokinetic analysis enabled us to show that cytostatic activity of the 2 new AALPs is characterized by multiple "terminal points" as the drugs' action results in a G1 block, in a slow-down of the transition from late S to G2 followed by an accumulation of HT29 cells in the G2 phase of the cell cycle.

Adenocarcinoma↗
PubMed1995

Radiation-induced apoptosis: effects of cell age and dose fractionation.

The cell cycle dependence of radiation-induced apoptosis was measured using mitotically synchronized REC:myc(ch1) and Rat1:mycb cells. Cells in S and G2 phases were more susceptible; the apoptotic fraction was about 0.7-0.8 as compared to about 0.4 for G1 cells at a dose of 10 Gy. Two-dimensional cytofluorimetric analysis of cells, pulsed-labeled with bromodeoxyuridine and then irradiated with 10 Gy, showed both G1 and G2 blocks (6-8 h) for REC:myc(ch1) cells but only G2 block for Rat1:mycb cells. Consistent with these results, wild-type p53 and WAF1 (or p21), known to play a role in G1 delay, was induced by radiation in REC:myc(ch1) but not in Rat1:mycb cells. The cell cycle dependence of radiation-induced apoptosis and the absence of a G1 block for Rat1:mycb cells led to the prediction and observation of the novel "inverse split-dose effect," i.e., a radiation dose given in two equal halves separated by a few hours yielded a higher level of apoptosis relative to that resulting from the same total dose given all at once. This effect is due to cell cycle progression from G1 to the more sensitive S-G2 phase during the interval between the split doses. In contrast, the inverse split-dose effect for apoptosis is absent for REC:myc(ch1), due presumably to the radiation-induced G1 delay. Parallel split-dose experiments, but using clonogenic survival as end points, show recovery for REC:myc(ch1) cells but not for Rat1:mycb cells, reflecting the influence of split-dose, radiation-induced apoptosis.

Animals↗
PubMed1980

[Periodization of the postnatal proliferative activity in the rat retinal pigment epithelium detected by a method of experimental microphthalmia].

The dynamics of postnatal proliferative activity (PA) in the retinal pigment epithelium (RPE) and of its dependence on the general eye growth factor (intraocular pressure) was studied by means of 3H-thymidine autoradiography and experimental microphtalmia (lens removal from the eyes of the 1 and 4 days old rats). The regulation of RPE growth by the intraocular pressure was shown to be connected with the control of the number of cells by means of stimulation of their entry in S phase. The number of binucleated cells, formed as a result of acytokinetic mitosis, reflected the minimal number of cells proceeded through the reproduction cycle and was a weighted average, constant for each age and RPE zone. The first period of PA coincided with the most intensive growth of scleral part (2 to 5 days after birth) and was characterized by independence from the intraocular pressure and differences in PA intensity in different RPE zones (the highest in the central zone and dorsal and temporal regions of the equatorial zone). The second period (5 to 11 days) was dependent from the intraocular pressure and characterized by the levelling and decrease of PA in all RPE zones. The postnatal PA in RPE was characterized by a long G2 phase and a short G1 phase. The functional importance of PA and mass polyploidization of cells in RPE is discussed in the light of G2 phase specificity for the differentiating effect of melanotropic hormones on the pigment cells.

Animals↗
PubMed1998

Effects of daunorubicin on cell growth, cell cycle and induction of apoptosis in HL-60 cells.

Administration of daunorubicin (DNR) at over 3.5 x 10(-8)M has been reported to block cells at G2 phase, but the precise mechanism of cell death induced by DNR is not well known. In this study effects of DNR at various concentrations on cell growth, cell cycle and induction of apoptosis in human leukemia cell line HL-60 cells were investigated. Administration of DNR at a high concentration (3.0 x 10(-8)M) inhibited cell growth to 3% as compared with untreated cells, blocked the cell cycle at G2 phase and induced cell-cycle non-specific apoptosis. Administration of DNR at a lower concentration (1.0 x 10(-8)M) inhibited cell growth to 77%, induced cell-cycle nonspecific apoptosis but did not produce G2 arrest. A longer duration of exposure to DNR was required to induce apoptosis by the lower concentration of DNR than by the higher concentration. These findings indicate that the effect of DNR on cell growth is caused by both G2 arrest and induction of apoptosis and that DNR induced apoptosis without G2 arrest. Moreover, continuous administration of a low concentration of DNR which has been considered to have no anticancer effect might be useful for treatment of leukemia and related diseases.

Apoptosis↗
PubMed1988

The relationship of DNA and chromosome damage to survival of synchronized X-irradiated L5178Y cells. II. Repair.

The purpose of this study was to investigate the role of DNA and chromosome repair in determining the difference in radiosensitivity between a radiosensitive murine leukemic lymphoblastoid cell line, L5178Y-S, and its radioresistant counterpart, L5178Y-R. Populations of cells in the G1 or G2 phase of the cell cycle were obtained by centrifugal elutriation and irradiated with X-ray doses up to 10 Gy and allowed to repair at 37 degrees C for various periods. The kinetics of DNA double-strand break repair was estimated using the DNA neutral filter elution method, and the kinetics of chromosome repair was measured by premature chromosome condensation. L5178Y-S cells exhibited decreased repair rates and limited repair capacity at both the DNA and chromosome level in both G1 and G2 phases when compared to L5178Y-R cells. For the repair-competent L5178Y-R cells, the rate of DNA repair was similar in G1 and G2 cells and exhibited both fast and slow components. While the kinetics of chromosome break repair in G1 cells was similar to that of DNA repair, chromosome repair in G2 cells had a diminished fast component and lagged behind DNA repair in terms of fraction of damage repaired. Interestingly, concomitant with a diminished repair capacity in L5178Y-S cells, the number of chromatid exchanges in G2 cells increased with time, whereas it remained constant with repair time in L5178Y-R cells. These results suggest that the basis for the exceptional radiosensitivity of L5178Y-S cells is a defect in the repair of both DNA double-strand breaks and chromosome damage.

Animals↗
PubMed2003

Fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro.

PURPOSE: Cell-extracellular matrix (ECM) interactions are thought to mediate drug and radiation resistance. Dependence of cell survival, beta1-integrin expression and cell cycling on the ECM proteins and beta1-integrin ligands fibronectin (FN) and laminin (LA) were examined in malignant and normal cells exposed to the cytotoxic drug Ukrain plus/minus irradiation. MATERIALS AND METHODS: Human A549 lung cancer and MDAMB231 (MDA231) breast cancer cells and normal fibroblasts (HSF1) grown on FN, LA, bovine serum albumin (BSA) or polystyrene were treated with Ukrain (1 microg ml(-1), 24 h) plus/minus irradiation (2-8 Gy) and the effects studied using colony formation assays, flow cytometry (beta1-integrin, DNA analysis) and adhesion assays. RESULTS: FN and LA reduced the cytotoxic effect of single Ukrain treatment compared with polystyrene and BSA. FN and LA also abolished Ukrain-dependent radiosensitization in A549 cells and decreased the radiosensitivity of MDA231 and HSF1 cells. Single Ukrain exposure on polystyrene significantly reduced beta1-integrin expression and promoted G2-phase accumulation of A549 cells. In contrast, Ukrain-treated MDA231 and HSF1 cells showed elevated beta1-integrin expression and no Ukrain-specific cell cycle effect. Under Ukrain-radiation exposure, irradiation, FN or LA abolished Ukrain-mediated reduction of beta1-integrin expression and G2-phase accumulation in A549 cells, whereas in MDA231 cells and fibroblasts beta1-integrin expression and cell cycle distribution were stabilized. Cell adhesion to FN or LA was significantly impaired (A549) or improved (MDA231, HSF1) upon Ukrain treatment. CONCLUSIONS: The data corroborate the findings of other groups that cell adhesion-mediated resistance to either single or combined drug and radiation exposure is tightly correlated to specific ECM proteins. By demonstrating a strong modulatory impact of FN and LA on the radiosensitivity-modifying activity of the drug Ukrain, the set findings are also highly important for the assessment of drug and radiation effects within in vitro cytotoxicity studies. The data give the first mechanistic insights into specific FN- and LA-modulated cellular resistance mechanisms as well as into the important role for beta1-integrins using the unique cytotoxic and radiosensitivity-modifying drug Ukrain.

Alkaloids↗
PubMed2000

RNA polymerase III transcription: its control by tumor suppressors and its deregulation by transforming agents.

The level of RNA polymerase (pol) III transcription is tightly linked to the rate of growth; it is low in resting cells and increases following mitogenic stimulation. When mammalian cells begin to proliferate, maximal pol III activity is reached shortly before the G1/S transition; it then remains high throughout S and G2 phases. Recent data suggest that the retinoblastoma protein RB and its relatives p107 and p130 may be largely responsible for this pattern of expression. During G0 and early G1 phase, RB and p130 bind and repress the pol III-specific factor TFIIIB; shortly before S phase they dissociate from TFIIIB, allowing transcription to increase. At the end of interphase, when cells enter mitosis, pol III transcription is again suppressed; this mitotic repression is achieved through direct phosphorylation of TFIIIB. Thus, pol III transcription levels fluctuate as mammalian cells cycle, being high in S and G2 phases and low during mitosis and early G1. In addition to this cyclic regulation, TFIIIB can be bound and repressed by the tumor suppressor p53. Conversely, it is a target for activation by several viruses, including SV40, HBV, and HTLV-1. Some viruses also increase the activity of a second pol III-specific factor called TFIIIC. A large proportion of transformed and tumor cell types express abnormally high levels of pol III products. This may be explained, at least in part, by the very high frequency with which RB and p53 become inactivated during neoplastic transformation; loss of function of these cardinal tumor suppressors may release TFIIIB from key restraints that operate in normal cells.

Animals↗
PubMed1993

Replication-dependent sister chromatid recombination in rad1 mutants of Saccharomyces cerevisiae.

Homolog recombination and unequal sister chromatid recombination were monitored in rad1-1/rad1-1 diploid yeast cells deficient for excision repair, and in control cells, RAD1/rad1-1, after exposure to UV irradiation. In a rad1-1/rad1-1 diploid, UV irradiation stimulated much more sister chromatid recombination relative to homolog recombination when cells were irradiated in the G1 or the G2 phases of the cell cycle than was observed in RAD1/rad1-1 cells. Since sister chromatids are not present during G1, this result suggested that unexcised lesions can stimulate sister chromatid recombination events during or subsequent to DNA replication. The results of mating rescue experiments suggest that unexcised UV dimers do not stimulate sister chromatid recombination during the G2 phase, but only when they are present during DNA replication. We propose that there are two types of sister chromatid recombination in yeast. In the first type, unexcised UV dimers and other bulky lesions induce sister chromatid recombination during DNA replication as a mechanism to bypass lesions obstructing the passage of DNA polymerase, and this type is analogous to the type of sister chromatid exchange commonly observed cytologically in mammalian cells. In the second type, strand scissions created by X-irradiation or the excision of damaged bases create recombinogenic sites that result in sister chromatid recombination directly in G2. Further support for the existence of two types of sister chromatid recombination is the fact that events induced in rad1-1/rad1-1 were due almost entirely to gene conversion, whereas those in RAD1/rad1-1 cells were due to a mixture of gene conversion and reciprocal recombination.

Cell Cycle↗
PubMed2000

High pressure sensitizes murine erythroleukemia cells to caffeine-induced premature mitosis.

Murine erythroleukemia (MEL) cells were exposed to a high pressure of 80 MPa or aphidicolin (APH), DNA polymerase inhibitor. The effects of caffeine on cell cycle were examined using these cells. During the culture of 80 MPa-treated MEL cells at atmospheric pressure, the cells arrested in the G2 phase, and cyclin B and hyperphosphorylated p34(cdc2) were accumulated. Namely, maturation promoting factor (MPF) composed of p34(cdc2) and cyclin B was inactive. However, upon exposure to caffeine, these cells entered prematurely into mitosis by activating MPF. Caffeine-induced premature mitosis was suppressed by butyrolactone I and orthovanadate. On the other hand, APH-treated MEL cells, which were not exposed to 80 MPa, were not so sensitive to caffeine-induced premature mitosis despite cyclin B accumulation. In this case, dephosphorylation of p34(cdc2) was not induced by caffeine. Interestingly, caffeine-induced premature mitosis in the 80 MPa-treated cells was also suppressed by APH. These results suggest that the premature mitosis of 80 MPa-treated MEL cells by caffeine is induced by active MPF, and that APH-sensitive molecules such as DNA polymerase may also play an important role in the checkpoint that controls the transition from G2 to M phase.

Animals↗
PubMed2005

Inhibitory effects of Celecoxib and Sc-58125 on proliferation of human carcinoma of larynx Hep-2 in vitro.

The inhibitory effects of two kinds of selective cyclooxygenase-2 inhibitors on the proliferation of human carcinoma of larynx Hep-2 in vitro and their corresponding mechanisms were investigated. Hep-2 cells were cultured with two kinds of selective cyclooxygenase-2 inhibitors (Sc-58125 and Celecoxib) at various concentrations for 24 h. Morphological changes were observed under the phase microscopy and the growth suppression was detected by using MTT colorimetric assay. Apoptotic DNA fragments were observed by agarose gel electrophoresis, and the cell cycle and apoptotic rate were detected by flow cytometry (FCM) respectively. Hep-2 cells became rounded and detached from the culture dish after being treated with Celecoxib for 24 h, however, they remained morphologically unchanged with Sc-58125. Sc-58125 could increase G2 phase cells, whereas, Celecoxib rose G1 phase cells. Both of the two effects were dose-dependent. Moreover, the Hep-2 cells cultured with 50 micromol/L and 100 micromol/L Celecoxib showed obvious apoptosis, with the nuclear DNA of cells exhibiting characteristic DNA ladder. So Sc-58125 could inhibit the proliferation of Hep-2 cells by altering the G2 phase cells. However, Celecoxib had the same effect by changing the G1 phase cells and inducing apoptosis at higher concentration.

Antineoplastic Agents↗
PubMed2003

Alterations in radiation induced cell cycle perturbations by 2-deoxy-D-glucose in human tumor cell lines.

In the present studies, effects of glucose analogue, 2-deoxy-D-glucose (2-DG) on radiation-induced cell cycle perturbations were investigated in human tumor cell lines. In unirradiated cells, the levels of cyclin B1 in G2 phase were significantly higher in both the glioma cell lines as compared to squamous carcinoma cells. Upon irradiation with Co60 gamma-rays (2 Gy), the cyclin B1 levels were reduced in U87 cells, while no significant changes could be observed in other cell lines, which correlated well with the transient G2 delay observed under these conditions by the BrdU pulse chase measurements. 2-DG (5 mM, 2 hr) induced accumulation of cells in the G2 phase and a time-dependent increase in the levels of cyclin B1 in both the glioma cell lines, while significant changes could not be observed in any of the squamous carcinoma cell lines. 2-DG enhanced the cyclin B1 level further in all the cell lines following irradiation, albeit to different extents. Interestingly, an increase in the unscheduled expression of B1 levels in G1 phase 48 hr after irradiation was observed in all the cell lines investigated. 2-DG also increased the levels of cyclin D1 at 24 hr in BMG-1 cell line. These observations imply that 2-DG-induced alterations in the cell cycle progression are partly responsible for its radiomodifying effects.

Carcinoma, Squamous Cell↗