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At least 19 recordsLinked to original sources
PubMed1995

Characterization of alkylating versus intercalating anticancer drug-induced effects on cell survival, cell cycle kinetic and morphonuclear pattern of three neoplastic cells lines growing in vitro.

PURPOSE: The influence of three alkylating and three intercalating anticancer drugs on cell survival, cell cycle kinetics and chromatin patterns was monitored in vitro on three neoplastic cell lines. METHODS: This monitoring was carried out by means of the digital cell image analysis of Feulgen-stained nuclei. RESULTS: Results show that in term of cytotoxicity, the intercalating drugs were more potent than the alkylating ones. As for the cell kinetics assessment, most of the experimental conditions led to a blockage of the cells in the G2 phase of the cell cycle. A study of chromatin patterns by means of digital cell image analysis enabled us to describe 15 morphonuclear parameters. The results show that the drugs tested induced specific morphonuclear modifications, e.g. an increase in nuclear size. The 15 morphonuclear parameters were submitted to multivariate analyses, i.e. principal-components analyses followed by the canonical transformation of the data. The results of these multivariate analyses enabled us to discriminate between the alkylating and the intercalating drugs. CONCLUSIONS: We conclude that it would be possible to "diagnose" the mechanism of action of DNA interacting agents (alkylating or intercalating drugs) by means of the combination of digital cell image and multivariate analysis.

Adenocarcinoma↗
PubMed1983

Effects of vincristine on cell survival, cell cycle progression, and mitotic accumulation in asynchronously growing Sarcoma 180 cells.

The effects of vincristine (VCR) on cell survival, cell cycle progression, DNA synthesis, and metaphase accumulation were studied in relation to drug concentration and drug exposure duration in Sarcoma 180 cells in vitro. VCR was found to affect cells in interphase, producing a transient G2 block at all drug concentrations and drug exposure durations studied. VCR did not affect DNA synthesis directly. Increases in the metaphase index were delayed and always peaked at approximately 8 hr after drug removal, regardless of the duration of drug exposure. Increases in the metaphase index of sufficient magnitude to be commensurate with VCR lethality were observed only with prolonged drug exposure. VCR produced both nuclear fragmentation and polyploidy. The proportion of cells undergoing polyploidy increased progressively with increasing drug exposure duration. Interference with cytokinesis during prolonged VCR exposure may represent a lethal effect of VCR that is separate from its short-term effects. This could serve as the basis for the clinical study of the antitumor effects of prolonged VCR infusions.

Animals↗
PubMed2002

Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action.

Studies from our laboratory have demonstrated that the major green tea polyphenol, (-)-epigallocatechin 3-gallate (EGCG), exerts potent neuroprotective actions in the mice model of Parkinson's disease. These studies were extended to neuronal cell culture employing the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA). Pretreatment with EGCG (0.1-10 microm) attenuated human neuroblastoma (NB) SH-SY5Y cell death, induced by a 24-h exposure to 6-OHDA (50 microm). Potential cell signaling candidates involved in this neuroprotective effect were further examined. EGCG restored the reduced protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) activities caused by 6-OHDA toxicity. However, the neuroprotective effect of EGCG on cell survival was abolished by pretreatment with PKC inhibitor GF 109203X (1 microm). Because EGCG increased phosphorylated PKC, we suggest that PKC isoenzymes are involved in the neuroprotective action of EGCG against 6-OHDA. In addition, gene expression analysis revealed that EGCG prevented both the 6-OHDA-induced expression of several mRNAs, such as Bax, Bad, and Mdm2, and the decrease in Bcl-2, Bcl-w, and Bcl-x(L). These results suggest that the neuroprotective mechanism of EGCG against oxidative stress-induced cell death includes stimulation of PKC and modulation of cell survival/cell cycle genes.

Catechin↗
PubMed2006

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development.

The chemokine stromal cell-derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

Animals↗
PubMed1986

Low dose-rate effects of cesium-137 and iodine-125 on cell survival, cell progression, and chromosomal alterations.

Chinese hamster ovary (CHO-AA8) cells in exponential growth were exposed to graded doses of radiation from iodine-125 (I-125) or cesium-137 (Cs-137) at various low dose rates, then monitored for cell number and clonogenic integrity. Cellular kinetics and the induction of sister chromatid exchanges and chromosomal aberrations were evaluated in cells after irradiation. Dose rates within the range 3-23 cGy/h had little effect on these fast growing cells but there was significant cell killing at dose rates of 33-70 cGy/h. The relative biological effectiveness (RBE) values for I-125 relative to Cs-137, calculated from the cell growth curves and the percentage of plating efficiencies of irradiated cells as a fraction of control, were 1.28 and 1.5., respectively, and did not vary over the dose-rate range from 3 to 70 cGy/h. The percentage of mitoses with chromosomal aberrations increased as a function of dose, but showed little if any change with dose rate. Cells passing through two cell cycles after irradiation also showed dose-dependent increases in the frequency of sister chromatid exchanges. That is, viable cells continue to show the effects of low dose-rate irradiation at the DNA level long after irradiation is concluded. Frequencies of cells in mitosis (mitotic index) and of cells incorporating bromodeoxyuridine (BrdU) (cycling S phase cells) indicated that low dose-rate I-125 irradiation produced a much more profound delay than low dose-rate of Cs-137 irradiation. This more pronounced inhibition may play a significant role in enhancing the effect of low dose rate I-125 in a clinical situation.

Animals↗
PubMed2005

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile.

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan --> gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine --> topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan --> gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression.

Antimetabolites, Antineoplastic↗
PubMed2000

Metabolic aspects of programmed cell survival and cell death in the heart.

Normal cardiac function requires a tight interaction between metabolism, contractile function and gene expression. The main perturbation challenging this equilibrium in vivo is ischemia, which alters energy flux through the control of key enzymes. The review highlights metabolic imprints and energetic aspects of programmed cell survival, programmed cell death, and of necrosis. When sustained and severe, ischemia leads to a total collapse of energy transfer, to the accumulation of metabolic endproducts, and to the development of myocardial necrosis. When moderate, ischemia results in a coordinated cellular response including enhanced anaerobic glucose metabolism, a modification of cardiac gene expression, and the development of specific mechanisms for programmed cell survival (preconditioning, stunning, hibernation). Repetitive stress results in a decrease of contractile function, a downregulation of gene expression and an impairment of energy transfer, which eventually cause the heart to fail. When the failing heart becomes energy-depleted, the programs of cell survival are no longer operational and programmed cell death ensues. To define the point of departure from programmed cell survival to cell death remains a major challenge.

Adenosine Triphosphate↗
PubMed1988

Effects of U-71,184 and several other CC-1065 analogues on cell survival and cell cycle of Chinese hamster ovary cells.

CC-1065 is a very potent antitumor antibiotic which selectively binds in the minor groove of DNA with alkylation at N-3 of adenine. Since therapeutic doses of CC-1065 caused delayed deaths in mice, analogues were synthesized, some of which had significant antitumor activity. The effects of several of these analogues on inhibition of CHO cell survival, cell progression, and their phase-specific toxicity are reported. CC-1065, U-66,664, U-66,819, U-66,694, and U-71,184 all have a left hand segment with an intact cyclopropyl group but have different tail segments. Lethality of these compounds after 2 h drug exposure was in the following order (50% lethal dose in nM in parentheses): CC-1065 (0.06) greater than U-71,184 (1.3) greater than U-66,694 (3.2) greater than U-68,819 (171) greater than U-66,664 (greater than 1200). In general, these compounds did not inhibit progression from G1 to S but slowed progression through S and blocked cells in G2-M. The phase-specific toxicity of U-71,184 and U-66,694 was different from that of CC-1065. CC-1065 was most cytotoxic to cells in M and early G1 and toxicity decreased as cells entered late G1 and S. In contrast, U-66,694 and U-71,184 were most toxic to cells in late G1. The biochemical and cellular effects of U-71,184 were then studied in detail since it was the most active among these analogues. After a 2-h exposure to 3 ng/ml U-71,184, 90% cell kill or growth inhibition was observed whereas 100 ng/ml was needed for similar inhibition of DNA and RNA synthesis. This discrepancy between the doses suggested that inhibition of nucleic acid synthesis may not be causally related to lethality. Further studies showed that when drug was removed after 2 h exposure, DNA synthesis continued to be inhibited whereas RNA and protein synthesis reached levels higher than the control. Therefore, it is likely that at cytotoxic doses the low level of inhibition of DNA synthesis combined with the stimulation of RNA and protein synthesis leads to unbalanced growth and cell death.

Animals↗
PubMed2005

Clinging to life: cell to matrix adhesion and cell survival.

Cell to matrix adhesion regulates cellular homeostasis in multiple ways. Integrin attachment to the extracellular matrix mediates this regulation through direct and indirect connections to the actin cytoskeleton, growth factor receptors, and intracellular signal transduction cascades. Disruption of this connection to the extracellular matrix has deleterious effects on cell survival. It leads to a specific type of apoptosis known as anoikis in most non-transformed cell types. Anchorage independent growth is a critical step in the tumorigenic transformation of cells. Thus, breaching the anoikis barrier disrupts the cell's defenses against transformation. This review examines recent investigations into the molecular mechanisms of anoikis to illustrate current understanding of this important process.

Actins↗
PubMed2005

Gap junctions and the propagation of cell survival and cell death signals.

Gap junctions are a unique type of intercellular channels that connect the cytoplasm of adjoining cells. Each gap junction channel is comprised of two hemichannels or connexons and each connexon is formed by the aggregation of six protein subunits known as connexins. Gap junction channels allow the intercellular passage of small (< 1.5 kDa) molecules and regulate essential processes during development and differentiation. However, their role in cell survival and cell death is poorly understood. We review experimental data that support the hypothesis that gap junction channels may propagate cell death and survival modulating signals. In addition, we explore the hypothesis that hemichannels (or unapposed connexons) might be used as a paracrine conduit to spread factors that modulate the fate of the surrounding cells. Finally, direct signal transduction activity of connexins in cell death and survival pathways is addressed.

Animals↗
PubMed2000

Increased repair and cell survival in cells treated with DIR1 antisense oligonucleotides: implications for induced radioresistance.

PURPOSE: To determine whether repression of a recently isolated, X-ray-responsive gene, DIR1, using antisense oligonucleotides could affect clonogenic cell survival and repair of DNA strand breaks and have a possible role in the mechanism underlying the phenomenon of 'induced radioresistance' (IRR). MATERIALS AND METHODS: Three cell lines, V79, RT112 and UM-UC-3, which are known to exhibit low-dose hypersensitivity (HRS) and induced radioresistance (IRR), and the radiosensitive cell line ATBIVA, were transfected with antisense oligonucleotides directed towards the DIR1 gene. Scrambled oligonucleotides were used as controls. DNA single-strand break (ssb) repair, using the alkaline comet assay, and cell survival using a standard clonogenic assay was measured after exposure to X-rays. RESULTS: Following treatment with 4Gy X-rays, the V79, RT112 and UM-UC-3 cell lines all exhibited significantly increased rates of ssb repair after transfection with DIR1 antisense oligonucleotides compared with cells transfected with scrambled oligonucleotides. They also demonstrated significantly enhanced survival after exposure to 2 Gy X-rays; the radiosensitive ATBIVA cells did not show these effects. CONCLUSIONS: Repression of the DIR1 gene product leads to an increase in the rate of repair and cell survival in three radioresistant cells lines but not in the radiosensitive ATBIVA cell line. Because DIR1 is repressed by X-rays in the dose range where IRR is observed, it may represent a candidate gene involved in the IRR phenomenon.

Animals↗
PubMed1999

Pharmacodynamics and toxicodynamics of drug action: signaling in cell survival and cell death.

In therapeutic response to drugs, the plasma concentration range leads to the establishment of a safe and effective dosage regimen. Our hypothesis is that by studying drug concentration-dependent effect on signal transduction mechanisms, a better understanding of the beneficial pharmacodynamic and adverse toxicodynamic responses elicited by the drug may be achieved. Using two classes of chemopreventive compounds (phenolic antioxidants and isothiocyanates), we illustrate the potential utility of two signal transduction pathways elicited by these agents to predict the pharmacodynamic effect (induction of Phase II drug metabolizing enzymes) and the potential toxicodynamic response (stimulation of caspase activity and cytotoxic cell death). At lower concentration, phenolic antioxidants and isothiocyanates activate mitogen-activated protein kinase (MAPK; extracellular signal-regulated protein kinase 2, ERK2; and c-Jun N-terminal kinase 1, JNK1) in a concentration-and time-dependent manner. The activation of MAPK by these compounds may lead to the induction of cell survival/protection genes such as c-jun, c-fos, or Phase II drug metabolizing enzymes. However, at higher concentrations, these agents activate another signaling molecule, ICE/Ced3 cysteine protease enzymes (caspases) leading to apoptotic cell death. The activation of these pathways may dictate the fate of the cells/tissues upon exposure to drugs or chemicals. At lower concentrations, these compounds activate MAPK leading to the induction of Phase II genes, which may protect the cells/tissues against toxic insults and therefore may enhance cell survival. On the other hand, at higher concentrations, these agents may activate the caspases, which may lead to apoptotic cell death, and have toxicity. Understanding the activation of these and other signal transduction events elicited by various drugs and chemicals may yield insights into the regulation of gene expression of drug metabolizing enzymes and cytotoxicity. Thus, the study of signaling events in cell survival (hemeostasis) and cell death (cytotoxicity) may have practical application during pharmaceutical drug development.

Animals↗
PubMed1975

The effect of an hypoxic cell sensitizer on tumour growth delay and cell survival. Implications for cell survival in situ and in vitro.

A comparison has been made of the effects of the 2-nitroimidazole Ro-07-0582 on tumour growth delay after irradiation and tumour cell survival in vitro after irradiation in vivo. This compound has previously been shown to be a specific sensitizer of hypoxic cells. A dose of 1 mg/g body weight gave an enhancement ratio of 2-2 for both growth delay and cell survival in a system where high pressure oxygen has been shown to have no effect. However, while the hypoxic fraction in the tumour was estimated to be less then 10% from the growth delay curves, the survival curves gave a value in excess of 50%. This discrepancy probably reflects differences in the response of cells left in situ or removed and assayed in vitro.

Animals↗
PubMedDate not supplied

Transplantation of virally transduced cells into the dermis of immunocompetent and immunodeficient (SCID) mice to determine gene expression profile and differential donor cell survival.

Cell therapy and bioengineering hold great promise as therapeutic approaches using cells and cell-derived factors to treat various pathologic or trauma-induced states. One possible application is the transplantation of cells into wounded tissue to help regulate tissue repair. Cells engineered for optimal wound healing may help to minimize scarring following surgery or to enhance the rate of healing of chronic wounds. The purpose of the current study was to determine the effect of a viral insert, the LacZ-bearing, first generation adenovirus AdRGD, on the survival of dermally transplanted murine skin allogenic fibroblasts. The LacZ insert facilitated quantitation of both cell survival and gene expression and was used here to measure viable cell number. In addition to bearing the LacZ marker, the AdRGD vector is capable of carrying therapeutic gene inserts, so this study tested the feasibility of gene therapy for wound healing. Murine skeletal muscle PP6 (i.e., Pre-Plate 6) myogenic stem cells served as an alternate donor cell type. Cells were labeled with the LacZ-bearing AdRGD adenovirus vector and injected (50,000 cells/site) into the dorsal skin of adult normal, immunocompetent mice as well as in immunodeficient SCID mice. Skin biopsies were taken on days 0, 1, 2, 3, and 7 post-transplant, and assayed for LacZ expression. Soon after transplant (day 1), cell numbers underwent a transient decrease, but by day 2 post-transplant they were present in appreciable numbers. Between days 2-7 post-transplant, both allogenic fibroblasts and PP6 myogenic stem cells maintained survivability in similar numbers. Further, survival of transplanted cell types was similar in both normal, immunocompetent as well as SCID mice during this time period. There were no signs of acute inflammation or rejection in any of the samples. This study shows that AdRGD-transduced cells are not immunogenic in the mouse skin model and the cells show similar survival for the first 7 days post-transplantation independent of the cell type or immunocompetence of the host.

Animals↗
PubMed1997

Integrin signaling: specificity and control of cell survival and cell cycle progression.

Integrin-mediated adhesion to the extracellular matrix plays an important role in regulating cell survival and proliferation. There is now increasing evidence that integrins activate shared as well as subgroup-specific signaling pathways. The signals from these adhesion receptors are integrated with those originating from growth factor and cytokine receptors in order to organize the cytoskeleton, stimulate mitogen-activated protein kinase cascades, and regulate immediate early gene expression. The repertoire of integrins and composition of the extracellular matrix appear to dictate whether a cell will survive, proliferate or exit the cell cycle and differentiate in response to soluble factors.

Animals↗
PubMed2001

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution.

The RBE of protons has been assumed to be equivalent to that of photons. The objective of this study was to determine whether radiation-induced DNA and chromosome damage, apoptosis, cell killing and cell cycling in organized epithelial cells was influenced by radiation quality. Thyroid-stimulating hormone-dependent Fischer rat thyroid cells, established as follicles, were exposed to gamma rays or proton beams delivered acutely over a range of physical doses. Gamma-irradiated cells were able to repair DNA damage relatively rapidly so that by 1 h postirradiation they had approximately 20% fewer exposed 3' ends than their counterparts that had been irradiated with proton beams. The persistence of free ends of DNA in the samples irradiated with the proton beam implies that either more initial breaks or a quantitatively different type of damage had occurred. These results were further supported by an increased frequency of chromosomal damage as measured by the presence of micronuclei. Proton-beam irradiation induced micronuclei at a rate of 2.4% per gray, which at 12 Gy translated to 40% more micronuclei than in comparable gamma-irradiated cultures. The higher rate of micronucleus formation and the presence of larger micronuclei in proton-irradiated cells was further evidence that a qualitatively more severe class of damage had been induced than was induced by gamma rays. Differences in the type of damage produced were detected in the apoptosis assay, wherein a significant lag in the induction of apoptosis occurred after gamma irradiation that did not occur with protons. The more immediate expression of apoptotic cells in the cultures irradiated with the proton beam suggests that the damage inflicted was more severe. Alternatively, the cell cycle checkpoint mechanisms required for recovery from such damage might not have been invoked. Differences based on radiation quality were also evident in the alpha components of cell survival curves (0.05 Gy(-1) for gamma rays, 0.12 Gy(-1) for protons), which suggests that the higher level of survival of gamma-irradiated cells could be attributed to the persistence of nonlethally irradiated thyrocytes and/or the capacity to repair damage more effectively than cells exposed to equal physical doses of protons. The final assessment in this study was radiation-induced cell cycle phase redistribution. Gamma rays and protons produced a similar dose-dependent redistribution toward a predominantly G(2)-phase population. From our cumulative results, it seems likely that a majority of the proton-irradiated cells would not continue to divide. In conclusion, these findings suggest that there are quantitative and qualitative differences in the biological effects of proton beams and gamma rays. These differences could be due to structured energy deposition from the tracks of primary protons and the associated high-LET secondary particles produced in the targets. The results suggest that a simple dose-equivalent approach to dosimetry may be inadequate to compare the biological responses of cells to photons and protons.

Animals↗
PubMed2005

Autophagy and signaling: their role in cell survival and cell death.

Macroautophagy is a vacuolar, self-digesting mechanism responsible for the removal of long-lived proteins and damaged organelles by the lysosome. The discovery of the ATG genes has provided key information about the formation of the autophagosome, and about the role of macroautophagy in allowing cells to survive during nutrient depletion and/or in the absence of growth factors. Two connected signaling pathways encompassing class-I phosphatidylinositol 3-kinase and (mammalian) target of rapamycin play a central role in controlling macroautophagy in response to starvation. However, a considerable body of literature reports that macroautophagy is also a cell death mechanism that can occur either in the absence of detectable signs of apoptosis (via autophagic cell death) or concomitantly with apoptosis. Macroautophagy is activated by signaling pathways that also control apoptosis. The aim of this review is to discuss the signaling pathways that control macroautophagy during cell survival and cell death.

Animals↗
PubMed2005

Autophagy-dependent cell survival and cell death in an autosomal dominant familial neurohypophyseal diabetes insipidus in vitro model.

Mutations in the human gene encoding the antidiuretic hormone vasopressin (VP) cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a rare inherited disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of VP from posterior pituitary nerve terminals. Work from our laboratories has shown that adFNDI, like other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's, is associated with autophagy. We have recently shown that the activation of autophagy in mouse neuroblastoma Neuro2a cells after adenoviral vector-mediated delivery of an adFNDI mutant VP transgene (Cys67stop) is a cell survival mechanism; its inhibition induces apoptosis. We now show that expression of Cys67stop sensitizes Neuro2a cells to the lethal effects of dopamine. This mode of cell death exhibits features typically associated with classical apoptosis. Yet inhibition of autophagy reversed these effects and rescued cell viability. We propose that autophagy-mediated cell death is a "two-hit" process: Following the cellular stress of the accumulation of a misfolded mutant protein, autophagy is prosurvival. However, a second insult triggers an autophagy-dependent apoptosis.

Adenoviridae↗