To see the other types of publications on this topic, follow the link: Cancer research; Cell death.
Dissertations / Theses on the topic 'Cancer research; Cell death'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Cancer research; Cell death.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Dremann, David Michael. "Pluronic Activity in Hyperthermia-induced Cancer Cell Death." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1247425426.
Full text
2
Ongkeko, Weg M. "The role of Cdc2 and p53 in cell cycle checkpoints and apoptosis." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244848.
Full text
3
McGuire, Karen M. "Characterization of Apatone and Tolecine Induced Cell Death Mechanisms in Bladder and Ovarian Cancer." Kent State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=kent1334356592.
Full text
4
Rong, Yiping. "Bcl-2 Regulates Proapoptotic Calcium Signals by Interacting with the Inositol 1, 4, 5-Trisphosphate Receptor." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1228322705.
Full text
5
Dhillon, Harsharan. "Mechanisms of Piperlongumine-Induced Cancer Cell Death." Diss., North Dakota State University, 2015. http://hdl.handle.net/10365/25178.
Full textAbstract:
Piperlongumine (PPLGM), a bioactive agent obtained from long pepper plants, possesses
potent antitumor activity by inducing reactive oxygen species (ROS). However, the mechanisms
for PPLGM?s antitumor actions are not well defined. We investigated PPLGM?s antitumor
effects and molecular mechanisms against pancreatic and colon cancer, two of the leading causes
of cancer death for both men and women in the U.S. We found that PPLGM activated a ROSmediated
DNA damage pathway that lead to pancreatic cancer cell death in vitro. Further, mice
treated with PPLGM showed reduced pancreatic tumor volume, which was associated with a
decrease in tumor cell proliferation and enhanced oxidative stress levels. To elucidate the target
pathways responsible for PPLGM-mediated cell death, RNA sequencing was performed. 684
genes were differentially expressed in pancreatic cancer cells treated with PPLGM compared to
the control. Genes related to ER-stress and UPR pathways were activated in PPLGM-treated
pancreatic cancer cells. To determine the therapeutic efficacy of PPLGM in combination with
currently used chemotherapy in vivo, an orthotopic mouse model of pancreatic cancer was used.
The combination of PPLGM with gemcitabine resulted in greater reduction of tumor weight and
volume than either agent alone, and PPLGM-treated mouse tumors showed decreased expression
of Ki-67, a proliferation marker. In vitro studies supported the in vivo results where the
combination of PPLGM with gemcitabine and erlotinib significantly decreased pancreatic cancer
cell viability and survival, and induced apoptosis compared to control cells or cells treated with
the chemotherapeutic agents alone. PPLGM inhibited the growth of colorectal cancer cells to a
greater degree than normal colon cells and activated p-ERK protein expression. The use of a
MEK inhibitor attenuated the activation of p-ERK and partially blocked PPLGM-mediated cell
death, indicating the involvement of the MEK/ERK pathway in colon cancer cell death. These
results suggest PPLGM holds potential as a therapeutic agent to treat pancreatic and colon cancer
in the clinics.North Dakota State University. Department of Biological Sciences
NDSU Graduate School Doctoral Dissertation Fellowship
NDSU Center for Protease Research COBRE (NIH 2P20 RR015566, P30 GM103332-01)
NDSU Development Foundation Centennial
Engebretson Family Research Endowments
6
Giampazolias, Evangelos. "Investigating non-apoptotic cell death in cancer." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8056/.
Full text
7
Prokop, Katherine Jane. "Cell Death Characterization In Tumor Constructs Using Irreversible Electroporation." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/51655.
Full textAbstract:
Pancreatic and prostate cancer are both prevalent cancers in the United States with pancreatic being one of the most aggressive of all cancers and prostate cancer being one of the most common, ranking as the number one cancer in men. Treatment of both cancers can be quite challenging as the anatomy of the pancreas and prostate, as well as the development and diagnosis of the disease can greatly limit treatment options. Therefore, it is necessary to develop new cancer treatments to help manage and prevent these cancers.
Irreversible electroporation is a new non-thermal focal ablation therapy utilizing short, pulsed electric fields to damage cell membranes leading to cell death. The therapy is minimally invasive, involving the insertion of needle electrodes into the region of interest and lasts less than two minutes. Heat sink effects that thermal therapies experience near large blood vessels do not affect irreversible electroporation. This allows the treatment to be used on tumors near vasculature as well as critical structures without harming these vital regions.
While irreversible electroporation is a promising new cancer therapy, further developments are necessary to improve treatment planning models. This work aims to further understand the electric field thresholds necessary to kill different types of cancer cells with a focus on pancreatic and prostate cancer. The work is done using an in vitro tumor (hydrogel) model as this model is better than traditional cell suspension studies, with added benefits over the immediate use of tissue and animal models.Master of Science
8
Świdziński, Jodi A. "Programmed cell death in Arabidopsis thaliana." Thesis, University of Oxford, 2003. http://ora.ox.ac.uk/objects/uuid:6e2580fc-8873-4722-89f7-b206d4be2a5f.
Full textAbstract:
Programmed Cell Death (PCD) describes an orderly cellular breakdown that occurs in both plants and animals throughout development and in response to biotic and abiotic stresses. The molecular machinery that functions in the induction and execution of animal PCD has been characterised in great detail. Conversely, few genes and proteins involved in plant PCD have been identified. While certain features of animal PCD may be conserved, the induction and execution of plant PCD is also likely to involve novel proteins and mechanisms. The aim of the work presented in this thesis was to investigate experimental approaches for studying plant PCD and to gain an understanding of the molecular mechanisms involved. To this end, an Arabidopsis thaliana cell suspension system was developed in which PCD could be induced by both a heat treatment (55°C, 10 min) and senescence (13 to 14 days-old). This system allowed for the molecular responses related to programmed cell death to be distinguished from those that were a specific response to the inducing stimulus. The Arabidopsis cell suspension system was utilised for an analysis of transcriptomic and proteomic changes that occur following the induction of PCD. A custom cDNA microarray analysis of ~100 putative cell death-related genes was used to measure the abundance of transcripts of these genes during PCD, and this work was extended to a whole-genome transcriptomic analysis of PCD. A number of candidate genes that may play a role in plant PCD were identified. These included those encoding antioxidant enzymes, cytosolic heat shock proteins, the mitochondrial adenine nucleotide translocase, ion transporters, a two-component response regulator (ARR4), several pathogenesis-related proteins, phospholipases and proteases, extracellular glycoproteins and enzymes (including a subtilisin-like protease, chitinases, and glucanases), and transcriptional regulators such as a homeobox leucine zipper and NAC-domain proteins. The induction and execution of plant PCD is also likely to involve mechanisms that are not transcriptionally regulated. A proteomic analysis of changes in the total cellular protein profile during heat- and senescence-induced PCD was therefore used to identify 12 proteins that are modulated in both systems and may play a PCD-specific role. These included the mitochondrial voltage-dependent anion channel (Athsr2), catalase, mitochondrial superoxide dismutase, an extracellular glycoprotein, and aconitase. Selected genes and proteins identified in the transcriptomic and proteomic analyses were further investigated in an attempt to define their role in plant PCD. Since PCD is difficult to quantitatively analyse at the whole-plant level, initially a strategy of transient expression of genes of interest in Arabidopsis protoplasts was adopted. However, it proved to be technically difficult to accurately quantify the number of dead cells in this system. As an alternative, Arabidopsis T-DNA insertional mutants within genes of interest were investigated for PCD-related phenotypes. Mutants in Senescence-Related Gene 3, the mitochondrial voltage-dependent anion channel (Athsr2), and cytosolic Heat shock protein 70-3 were isolated. The mutant lines were not visibly affected in their development, formation of xylem, onset and progression of senescence, or responses to abiotic and biotic stresses. This indicated that these genes are either not involved in the PCD pathway or that their functional role can be fulfilled by other gene products.
9
Li, Fangfang. "Regulation of pancreatic β-cell death and cancer cell migration by TPRM2 channels." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/13374/.
Full text
10
Hoopes, Justin Darrel. "Mechanisms of Induced Cell Death in Bluetongue Virus Challenged Human Cell Lines." DigitalCommons@USU, 2009. https://digitalcommons.usu.edu/etd/252.
Full textAbstract:
Bluetongue virus (BTV) is a pathogenic member of the Reoviridae family. BTV does not cause disease in humans, but is capable of selectively infecting and killing certain transformed human cell lines. Understanding BTV's oncotrophism may lead to new therapeutics for treating cancer. This study focused on the underlying mechanisms of BTV-induced cell death in carcinoma cell lines. It was our hypothesis that BTV infects human carcinoma transformed cells, produces mRNA and protein, induces a strong inflammatory response, induces mitogen activated protein kinase (MAPK)-based pro-apoptotic signaling, inhibits PKB-based signaling, and eventually kills the cell by inducing apoptosis.
Three carcinoma cell lines (A498, HEP-G2, and A549) were independently infected with BTV. In each cell line we determined: (1) cell viability over the course of infection; (2) BTV induced cytokine expression profile and magnitude of expression; (3) BTV viral RNA expression profile and magnitude of expression; (4) BTV viral protein expression profile and magnitude of expression; (5) changes in BTV induced cell death and cytokine expression in cells with protein kinase B (PKB), p38-MAPK, extracellular receptor kinase (ERK-1/2), stress-activated protein kinase (SAPK-JNK), Src kinase, platelet-derived growth factor receptor (PDGFR) kinase, epidermal growth factor receptor (EDGFR) kinase, or Janus kinase (JAK) activity inhibited; (6) intracellular changes in PKB, p38-MAPK, ERK-1/2, and SAPK-JNK phosphorylation as a result of BTV infection; and (7) BTV-induced changes in tyrosine phosphorylation.
We determined that BTV infects and kills all three cell lines in a cell line dependent manner. Relative cell death between cell lines was proportional to cytokine expression, but inversely proportional to viral protein expression. Only tyrosine kinase inhibitors influenced BTV-induced cell death and cytokine expression. Both A498 and A549 cells constitutively expressed phosphorylated PKB and p38 MAPK, of which both were de-phosphorylated during BTV infection. Tyrosine phosphorylation remained active, with elevated tyrosine phosphorylation exclusively in infected cells.
We conclude that BTV-induced cell death and cytokine expression are a function of the cell's response to infection and are directly related through intracellular signaling. These pathways are only partially poly I:C inducible, but include PKB and tyrosine kinase signaling.
11
Sistigu, Antonella. "Inflammatory and immune reactions in response to chemotherapy-induced cell death. Viral mimicry chemotherapy : ds RNA sensors and IFNAR signalling indispensable for immunogenic tumor cell death." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T052.
Full textAbstract:
Certains motifs moléculaires associés à la mort cellulaire semblent identifier les cancers prompts à répondre à une thérapie cytotoxique. Ceci en élaborant une réponse anti-tumorale basées sur une réponse T protectrice. Mon travail de thèse montre que le traitement par chimiothérapie immunogène active des voies moléculaires mimant une infection virale. Ceci conduit au niveau des cellules tumorales à une signalisation autocrine via l’IFNαβ / IFNAR1/2, initiée par la reconnaissance d’ARN double brin (dsRNA) endogène par les Récepteurs endosomaux de Reconnaissance des Motifs (PRRs). De façon plus détaillée, nous montrons que les axes TLR3/TRIF (senseurs endosomaux de dsRNA) et IFNAR1/2 (Récepteurs de l’IFN de Type I) doivent signaliser au niveau de la cellule tumorale pour que la chimiothérapie puisse aboutir à l’induction de l’axe CXCL10/CXCR3 et éliciter une réponse efficace in vivo. L’analyse du profil ARN de cellules tumorales Tlr3+/+ (mais pas Tlr3-/-) exposées aux anthracyclines a révélé une forte empreinte virale/IFN, indispensable à l’efficacité/activité anti-tumorale. Le fait d’affecter les axes TLR3 ou IFNAR1/2 au niveau tumorale soit à l’aide d’anticorps neutralisants, soit à l’aide de modèles KO abroge le relarguage de CXCL10 induit par la chimiothérapie, et ainsi la capacité à contrôler la pousse tumorale à moins que de l’IFNαβ ou du CXCL10 exogène soit co-administré aux anthracyclines. De plus la chimiorésistance des tumeurs traitées par des molécules n’induisant pas de signature virale peux être réversée par de l’IFN de Type I exogène. Enfin, la détection d’une signature IFN au niveau de biospies de cancers du sein humains permet de prédire la bonne réponse au traitement adjuvant par anthracyclines. D’un point de vue de l’évolution, alors que les tumeurs (comme les virus) ont élaboré des mécanismes pour échapper aux réponses IFN, la signature virale induite par la chimiothérapie devrait contribuer à contrecarrer cette immunoéditionDistinct cell death-associated molecular patterns might define cancers proned to respond to a cytotoxic therapy by mounting a protective T cell-based anticancer immunity. My PhD Thesis work shows that immunogenic chemotherapy phenocopies viral infection leading to autocrine IFNαβ/IFNAR1/2 signalling in tumor cells initiated by recognition of self dsRNA by endosomal pattern recognition receptors (PRRs). In detail, TLR3/TRIF (endosomal dsRNA sensors) and IFNAR1/2 (Type I IFN receptors) must signal within the tumor cells so that chemotherapy can induce downstream CXCL10/CXCR3 axis and elicit therapeutic responsiveness in vivo. RNA profiling of Tlr3+/+ (but not Tlr3-/-) tumor cells exposed to anthracyclines revealed a strong IFN/viral fingerprint, indispensable for the tumoricidal activity. Neutralization by antibodies or genetic defects affecting tumor –associated TLR3 or IFNAR1/2 compromised chemotherapy-induced CXCL10 release and tumor control unless exogenous IFNαβ or CXCL10 are concomitantly supplied to anthracyclines. Moreover, chemoresistance of tumors treated by drugs failing to induce a viral signature can be reversed by exogenous Type I IFN. Finally, the IFN fingerprint of human breast cancers allowed to predict tumors proned to benefit from adjuvant anthracyclines. From an evolutionary viewpoint, while tumors (like viruses) have evolved mechanisms to evade an IFN response, chemotherapy-induced viral mimicry might contribute to bypass such as immunoediting
12
Sukkurwala, Abdul Qader. "Autophagy : A New Modulator of Immunogenic Cell Death for Cancer Therapy." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T031.
Full textAbstract:
Certains agents chimiothérapeutiques tels que les anthracyclines ou l'oxaliplatine induisent une mort cellulaire immunogène, ce qui implique que les cellules mourrantes du patient servent de vaccin thérapeutique en stimulant une réponse immunitaire antitumorale. La mort cellulaire immunogène est caractérisée par la libération de signaux d'alarme par la cellule tumorale mourante qui permettent l’activation du système immunitaire. En premier lieu, l'exposition de la calréticuline à la surface de la cellule tumorale mourante va agir comme un signal de type «eat-me» pour les cellules dendritiques. Une fois relâchée, la protéine nucléaire HMGB1 se lie au récepteur TLR4 afin de faciliter la présentation antigénique. Les cellules mourantes vont également libérer de l'ATP qui agit sur les récepteurs P2X7 et active l’inflammasomme NLRP3, conduisant à la libération d'IL-1β et ainsi à l’activation des cellules T CD8+ productrices d’IFN-γ. L’autophagie est un mécanisme cellulaire qui est activé en réponse à la chimiothérapie. L'autophagie signifie «self-ating», il s'agit d'un processus cellulaire activé par diverses conditions de stress, par lequel les cellules peuvent dégrader les protéines et les organites. Il peut aussi être induit par un stress du réticulum endoplasmique. Ce dernier étant également impliqué dans l'exposition de la calréticuline pendant la mort cellulaire immunogène, nous avons au cours de cette étude cherché à déterminer le rôle de l'autophagie dans la mort cellulaire immunogène. Nous avons constaté que l'autophagie est nécessaire pour la libération de l'ATP après un traitement par des chimiothérapies immunogènes, en observant que le nockdown de gènes essentiels de l'autophagie limitait la sécrétion d'ATP. Nous avons également observé que des cellules déficientes pour l'autophagie traitées par une chimiothérapie immunogène sont incapables d’immuniser des souris contre une injection de cellules vivantes. En outre, les tumeurs déficientes pour l’autophagie ne répondent pas à un traitement systémique immunogène dans des souris immunocompétentes et continuent à proliférer en comparaison à des tumeurs “wild-type”. De plus, nous avons montré que les cellules déficientes pour l'autophagie ne sont pas en mesure de recruter des cellules dendritiques dans le lit tumoral ou d'induire l’activation des cellules T CD8+. A l'inverse, l'inhibition des enzymes de dégradation de l’ATP extracellulaire accroit les concentrations d'ATP dans les tumeurs déficientes pour l'autophagie, ce qui rétablit le recrutement des cellules immunitaires dans le lit tumoral et restaure la réponse chimiothérapeutique des cancers déficients pour l'autophagie. Ainsi, cette étude a montré l'importance de l'autophagie dans la réponse anti-tumorale spécifique, après traitement par des chimiothérapies immunogènes. Ces résultats ouvrent de nouvelles perspectives dans le concept de la mort cellulaire immunogèneIn recent years it has been demonstrated that some chemotherapeutic agents such as anthracyclines or oxaliplatin can induce a type of tumor cell death that is immunogenic, implying that the patient’s dying cancer cells serve as a therapeuticvaccine that stimulates an antitumor immune response, which in turn can control or eradicate residual cancer cells. Immunogenic cell death is characterized by the emission of danger signals from the dying tumor cell, which activate the immune system. At first the exposure of calreticulin, acts as an «eat-me» signal for dendritic cells (DCs). Once released, the nuclear protein HMGB1 binds to TLR4 on DCs, facilitating antigen processing and presentation. The dying tumor cells also releases ATP, which acts on P2X7 receptors on DCs and activates the NLRP3 inflammasome, leading to IL-1β release, necessary for IFN-γ-producing CD8+ T cell activation. Autophagy literally ‘self-eating’ is a cellular process activated in response to various conditions of cellular stress, whereby cells can liberate energy resources via the degradation of proteins and organelles. Recently autophagy has been found activated in response to chemotherapy and in this project we aimed to determine the potential role of autophagy in immunogenic cell death. We found that autophagy isrequired for the release of ATP in response to immunochemotherapeutic treatment, as we observed that the knockdown of essential autophagy-related genes abolished its secretion. We observed that autophagy deficient cells treated with immunogenic cell death inducers failed to immunize mice against a re-challenge with living cells. Furthermore, autophagy deficient tumors growing on immunocompetent mice did not respond to systemic immunogenic treatment and continued proliferating in contrast to autophagy proficient tumors. We showed that autophagy deficient cells were neither able to recruit DCs into the tumor bed nor to activate CD8+ T cells. Conversely, the inhibition of extracellular ATP degrading enzymes increased extracellular ATP concentrations in autophagy deficient tumors, which reestablished the recruitment of immune cells into the tumor bed, and restored chemotherapeutic responses in autophagy-deficient cancers. Altogether, this study showed the importance of autophagy in tumor-specific immune response after treatment with chemotherapy, thus giving new insights into the concept of immunogenic cell death
13
McDermott, Ultan. "The role of Fas in chemotherapy-induced colorectal cancer cell death." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426703.
Full text
14
Rogers, K. M. A. "Interferon-γ-mediated modulation of chemotherapy-induced breast cancer cell death." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432507.
Full text
15
Pike, Luke R. G. "The role of ATF4 in hypoxia-induced cell death in cancer." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:f32e03f9-0bd2-4dd1-8320-b082b9b2d363.
Full textAbstract:
Cancer cells survive the harsh oxygen and nutrient deprivation of the tumour microenvironment through the selection of apoptosis-resistant and glycolytic clones (Cairns et al., 2011; Graeber et al., 1996). In particular, the integrated stress response (ISR) has been shown to be pivotal in cancer cell survival in vivo and the resistance of cancer cells to therapy (Harding et al., 2003). In recent years, it has become apparent that increased autophagy is one mechanism by which the ISR can confer resistance to stress (Kroemer et al., 2010). ATF4 is a major transcriptional effector of the integrated stress response in severe hypoxia (<0.01% O₂). ATF4 is a well-established regulator of genes involved in oxidative stress, amino acid synthesis and uptake, lipid metabolism, protein folding, metastasis, and angiogenesis. Recent work has demonstrated an important role of ATF4 in promoting resistance to severe hypoxia through the transcriptional upregulation of MAP1LC3B and ATG5, essential components of the autophagy machinery (Rouschop et al., 2009b; Rzyski et al., 2010). In this work, the author describes several novel ATF4 target genes, and examines their role in the regulation of autophagy and the resistance of cancer cells to severe hypoxia. In the first part of this thesis, the author shows that three BH3-only members of the BCL-2 family of proteins--HRK, PUMA, and NOXA--are upregulated in response to severe hypoxia in an ATF4-dependent manner. In particular, the author shows that the poorly described BH3-only protein HRK is a direct target of transcriptional activation by ATF4, and that HRK induces autophagy in severe hypoxia, thereby providing the first evidence that the integrated stress response can transcriptionally trigger the autophagy process. In contrast to the previously described role of HRK in apoptosis, this thesis demonstrates that HRK can play a pro-survival role in the context of breast cancer cells. In the latter part of this thesis, the author identifies the essential autophagy gene ULK1 as an ISR target. The author shows that ULK1 expression in severe hypoxia is transcriptionally upregulated through direct activation by ATF4. The author identifies ULK1 as a crucial regulator of autophagy and mitophagy in both normoxia and severe hypoxia and shows that ULK1 plays a pivotal role in cancer cell survival. Furthermore, it is shown that human breast cancer patients with high levels of ULK1 relapse earlier than those with low levels of ULK1, thereby identifying ULK1 as a potential target for cancer therapy.
16
Mai, Thi Trang. "Cell death mechanisms of Marmycin A and Salinomycin in cancer cells." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS014.
Full textAbstract:
Le produit naturel salinomycine (SAL) est largement utilisé comme médicament anticoccidien et maintenant de plus en plus reconnu comme un agent destiné à réduire la proportion de population CD44⁺ / CD24⁻ cellules souches du cancer du sein. Ce facteur est important et intervient lors des rechutes des tumeurs du sein. Pour la première fois, nous avons décrit que l'action n’était pas ionophorique mais que le proton dit "éponge" de la salinomycine ciblait particulièrement la population des cellules souches du cancer. De plus, un analogue alcyne-amine synthétisé de la salinomycine a une action similaire à cette dernière sur la population CD44⁺ / CD24⁻ mais à une concentration inférieure : 30 nM pour 500 nM pour la salinomycine. En utilisant la méthode de clic-imagerie, nous avons observé le composé incolore dans les lysosomes et les auto-lysosomes. En augmentant le pH des vésicules acides, la salinomycine et ses analogues inhibent les activités des cathepsines B, L et D empêchant ainsi l'autophagie. Cette autophagie joue un rôle important dans la survie des cellules souches du cancer conduisant à une augmentation du facteur ROS et à une mort cellulaire par apoptose. Notre étude donne un aperçu du mécanisme par lequel la salinomycine élimine les cellules souches cancéreuses et propose des stratégies pour le traitement de cancers résistantsA natural product Salinomycin (SAL) is widely used as an anticoccidial drug now being increasingly recognized as an agent for reducing the proportion of CD44⁺/CD24⁻ breast cancer stem cell which is perceived as important factor for breast tumor relapse. We first time report that not ionophoric action but the proton “sponge” of SAL is responsible for distinguishingly targeting cancer stem cell population. In addition, one SAL-analog alkyne-amine performed the similar action with SAL on CD44⁺/CD24⁻ population but at much lower concentration than SAL, at 30 nM compare to 500 nM of SAL. Using click-imaging method we visually observed the colorless compound saturated in lysosomes and autolysosomes. By raising pH of acidic vesicles, SAL and its analogs inhibit cathepsin B, L, D activity preventing the autophagy which plays an important role in cancer stem cell maintain and survival thus lead to cell death via increasing ROS and apoptosis. Our study provides the insight mechanism how SAL actually eradicates cancer stem cells and suggests sharpened strategies for treating resistant cancers
17
Ajabnoor, Ghada. "Mechanism of cell death in drug resistant human breast cancer cells." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/842867/.
Full textAbstract:
Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), which plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic, or autophagic cell death (PCD II) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We studied in vitro cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 10- 20 fold) to paclitaxel, termed MCF-7TaxR. It has been reported that the absence of caspase-3 in parental MCF-7 cells (due to chromosome deletion) may explain why they recruit apoptotic and autophagic cell death following cytotoxic insult. We investigated the induction of apoptosis response to staurosporine and Z-VAD (pan-caspase inhibitor) using the Annexin V-FITC/PI assay and studied the effect of anti-Fas on MCF-7TaxR. Results demonstrated the lack of apoptosis induction in paclitaxel resistant breast cancer cells. The oligo GEAiTayRTM human apoptosis microarray and qPCR analysis confirmed the absence of caspase-7 and caspase-9 genes and many other apoptosis genes in MCF-7TaxR cells and their presence in MCF-7 cells. Western blot analysis also confirmed these results. Therefore, we investigated the presence of autophagic cell death in our MCF-7TaxR model. Flow cytometry using Acridine Orange assay, Beclin 1 and LC-3 protein detection, confocal microscopy and detection of Akt/mTOR expression. Data showed evidence of autophagic cell death in MCF-7TaxR cells in the absence of an apoptotic response. Collectively, these findings indicate the lack of involvement of caspase mediated cell death in a paclitaxel drug-resistant cancer cell line MCF-7TaxR, and presence of autophagic cell death as an alternative cell death mechanism.
18
Bretland, Amanda Jane. "Growth, survival and cell death in the epithelial cell lines HaCaT, HT29 and SW742." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286914.
Full text
19
Sivaramakrishnan, Aishwarya. "Characterizing the immunogenic cell death induced by Semliki Forest Virus in glioblastoma cell lines." Thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-446046.
Full textAbstract:
Glioblastoma is the most common primary brain tumor in humans and has a poor prognosis. Current therapies are not curative. Oncolytic viruses (OVs) are being investigated as tools to induce immunogenic cell death (ICD), cell death capable of activating the immune system. Semliki Forest Virus (SFV) strain 4 is an OV being investigated to treat glioblastoma. Previous studies in our lab have shown that SFV4 can induce ICD in human osteosarcoma (HOS) cells and ongoing in vivo studies show that SFV4 infected GL261 cell vaccination providesprotective immunity in mouse models. This study aimed to characterize the ICD induced by SFV4in glioblastoma cell lines, namely GL261, SB28 and CT2A, and to explain some of our in vivoobservations, namely why vaccination with SFV infected GL261 provides protective immunity but vaccination with infected CT2A and SB28 does not. Our in vitro studies found that GL261 is resistant to SFV4 while SB28 and CT2A are susceptible. We show that the virus can replicate in all three cell lines as seen by the presence of dsRNA, but that viral translation is delayed or inhibited in GL261 cells as not all cells positive for dsRNA were positive for SFV4 protein. Additionally, the type I interferon (IFN) pathway, responsible for antiviral defense, was highly upregulated in CT2A and SB28 but not as much in GL261 after infectionas seen by surveying IFIT1, IFITM3 and IFN-beta genes. Interferon stimulated genes (ISG) like CXCL10, a chemoattractant, was highly upregulated in GL261 after infection and might account for the protective immunity seen in vivo after vaccination. PDL1, an interferon stimulated gene responsible for self-tolerance, was highly upregulated in CT2A after infection. The IFN-beta ELISA revealed that both infected and uninfected GL261 cells produce IFN-beta suggesting a constitutively active pathway. Our DC phagocytosis assay showed that SFV4 infection of CT2A and SB28 cells induced a significant increase in DC phagocytosis and SFV4 infection of all three cell lines significantly increased DC maturation. We conclude that SFV4 infection of GL261 cells may induce ICD in vivo through a persistent viral infection and increased expression of CXCL10.
20
Lawlor, Martin Paul. "The role of radiation-induced cell death and resistance in non-small cell lung cancer." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579761.
Full textAbstract:
40% of all patients cured of cancer receive radiation therapy as a part of their treatment. However, acquired or intrinsic resistance remains a major obstacle in increasing this already effective treatment, particularly in the treatment of NSCLC. Therefore, new approaches are needed to increase its biological effectiveness. A major pathway of tumour radiation resistance is through inactivation of cell death pathways. Our aims were to develop and characterize an in vitro model system of NSCLC radiation resistance following fractionated exposures that mimic clinical treatment regimes, as well as, to manipulate the apoptotic and autophagic death pathways as a means to sensitize NSCLC to radiotherapy. We found that exposure to a series of fractionated treatments resulted in acquired resistance of NSCLC cell lines to IR. In addition, we found that cisplatin-resistant NSCLC lines, developed following similar fractionated exposures, were also radiation-resistant. Our results suggest that there may be common pathways of radiation/cisplatin-resistance, and by studying modes of cell death, we can target under-utilized cell death pathways to improve the efficacy of radiation treatment. We modulated apoptosis induction by inhibiting caspases (Z-VAD-fmk) and BcI-2 anti-apoptotic proteins (Obatoclax). Our results showed that apoptosis plays a minor role in radiation-induced cell death. While caspase and BcI-2 anti-apoptotic protein inhibition resulted in changes in apoptosis, we observed no change in clonogenic survival. We then targeted autophagy induction through the inhibition of mTOR by Rad001. We found that mTOR inhibition resulted in decreased autophagy, suggesting that autophagy was being utilized as a survival mechanism in NSCLC, thus causing a significant reduction in cell survival following IR treatment. However, in combination with IR, both Obatoclax and Rad001 did not cause an additive or synergistic increase in cell death. Cell cycle analyses revealed that alternative mechanisms of cell death such as mitotic catastrophe and senescence may play a more pivotal role in IR-induced cell death. Altogether, our studies reveal that NSCLC cells may undergo multiple cell death pathways in response to IR. Our fractionated model system, as a mimic of clinical acquired radiation-resistance, will facilitate further examination of the mechanisms of radiation resistance. And our findings suggest that manipulation of alternative death pathways (such as mitotic catastrophe and senescence) in NSCLC needs further examination as a target for tumour sensitization to radiotherapy.
21
Littlejohn, Alison F. "Investigations into the molecular mechanisms that regulate whether tumour necrosis factor (TNF) induces cell survival or cell death." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274803.
Full textAbstract:
TNFR2 can activate NR-kB independently of TNFR1 although to a lesser degree. It was also demonstrated that caspases and NF-kB do not interact directly as caspase inhibition could not prevent NF-kB activation. The interaction between caspases and MAP kinases in HeLa-TNFR2 cells was also investigated. It was shown that JNK activation in response to TNF was attenuated following caspase inhibition while p42/44 MAP kinase and p38 MAP kinase activation were unaffected by caspase inhibition (Littlejohn et al, 2002). Further to these studies TNF receptor associated cytoplasmic adaptor proteins, in particular TRAF1, TRAF2 and RIP, were investigated with a view to determining the molecular switch between life and death in HeLa-TNFR2 cells. It was established using immunoprecipitation that TNFR2 could associate with RIP, as could TRAF1 and TRAF2. However, on the whole this technique gave limited information and further experiments are required to determine more conclusively the interactions taking place between the adaptor proteins, TNFR1 and TNFR2. In order to investigate the molecular switch more effectively, TF-1 cells were used. It was already known that TF-1 cells proliferate in response to TNF it cultured in the absence of GMCSF however, if cultured in the presence of GMCSF then TNF stimulation induces apoptotic cell death. This model of TNF induced life versus death demonstrated that caspase mediated RIP cleavage only occurs in the death scenario. RIP degradation is accompanied by reduced NF-kB activation suggesting that NF-kB activation is indeed a protective mechanism. Although many different avenues have been investigated the main conclusions that can be drawn from these studies are that TNF can regulate NF-kB via TNFR1 and TNFR2 and that competent NF-kB activation is required to protect cancer cells from TNF induced death. Perhaps if it was possible to inhibit NF-kB then TNF could be used effectively as a cancer killing agent.
22
Martinsson, Petra 1974. "Pharmacological studies of CHS 828 and etoposide induced tumour cell death /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5157-8/.
Full text
23
Kelly, D. M. "Regulation of colorectal cancer cell death by the epidermal growth factor receptor." Thesis, Queen's University Belfast, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.479277.
Full text
24
Quarni, Waise. "VDR-RIPK1 Interaction and its Implications in Cell Death and Cancer Intervention." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6569.
Full textAbstract:
Receptor interacting protein kinase 1 (RIPK1) is an enzyme acting downstream of tumor necrosis factor alpha to control cell survival and death. RIPK1 expression has been reported to cause drug resistance in cancer cells; but so far, no published studies have investigated the role of RIPK1 in vitamin D action. In the present study, we investigated whether RIPK1 played any role in 1,25-dihydroxyvitamin D3 (1,25D3)-induced growth suppression. In our studies, RIPK1 decreased the transcriptional activity of vitamin D receptor (VDR) in luciferase reporter assays independently of its kinase activity, suggesting a negative role of RIPK1 in 1,25D3 action. RIPK1 also formed a complex with VDR and deletion analyses mapped the RIPK1 binding region to the C-terminal ligand-binding domain of VDR. Subcellular fractionation analyses indicated that RIPK1 increased VDR retention in the cytoplasm, which may account for the inhibition of VDR transcriptional activity. Consistent with the reporter analyses, 1,25D3-induced growth suppression was more pronounced in RIPK1-null mouse embryonic fibroblasts (MEF) and RIPK1 knockdown ovarian cancer cells than control cells. We have also shown that VDR was involved in RIPK1-mediated cell death pathway in a cell line specific manner. In vivo study showed that VDR deletion delayed the necroptotic response to tumor necrosis factor alpha in mice. Western blot analyses of platinum sensitive and resistant cell lines showed a correlation between RIPK1 expression and drug resistance, suggesting a possible role of RIPK1 in drug resistance. In conclusion, this study is the first to define RIPK1 as a VDR repressor, projecting RIPK1 depletion as a potential strategy to increase the potency of 1,25D3 and its analogs for cancer intervention.
25
Flynn, Patrick G. "Activation of Non-Muscle Myosin IIB Helps Mediate TNF-Alpha Cell Death Signaling." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/369.
Full textAbstract:
TNF-alpha can stimulate a variety of kinases with the ability to activate non-muscle myosin II. As a result, increases in actin filament formation and actomyosin contractility (AMC) have been reported in response to TNF-alpha. These events are thought to play an important role in mediating TNF-alpha induced apoptosis but how they do so is unclear. In this study we prevented non-muscle myosin II activation in response to TNF-alpha by treating cells with the myosin light chain kinase (MLCK) inhibitor ML-7 or through isoform specific siRNA knockdown of myosin IIA and IIB. We found that treatment with ML-7 or knockdown of myosin IIB, but not IIA, impaired the cleavage of caspase 3 and caspase 8 as well as nuclear condensation in response to TNF-alpha. During this cell death process myosin II seemed to function independent of AMC since treatment of cells with blebbistatin or cytochalasin D failed to inhibit TNF-alpha induced caspase cleavage. Immunoprecipitation studies revealed associations of myosin IIB with clathrin and FADD in response to TNF-alpha suggesting a role for myosin IIB in TNFR1 endocytosis and DISC formation. Taken together these findings suggest that myosin IIB activation promotes TNF-alpha cell death signaling in a manner independent of its force generating property.
26
Kosmacek, Elizabeth Anne Ianzini Fiorenza Mackey Michael A. "Live cell imaging technology development for cancer research." [Iowa City, Iowa] : University of Iowa, 2009. http://ir.uiowa.edu/etd/388.
Full text
27
Kosmacek, Elizabeth Anne. "Live cell imaging technology development for cancer research." Diss., University of Iowa, 2009. https://ir.uiowa.edu/etd/388.
Full textAbstract:
Live cell imaging is a unique tool for cellular research with a wide variety of applications. By streaming digital microscopic images an investigator can observe the dynamic morphology of a cell, track cell movement on a surface, and measure quantities or localization patterns of fluorescently labeled proteins or molecules. Digital image sequences contain a vast amount of information in the form of visually detectable morphological changes in the cell. We designed computer programs that allow the manual identification of visible events in live cell digital image sequences [Davis et al. 2007]. Once identified, the data are analyzed using algorithms to calculate the yield of individual events per cell over the time course of image acquisition. The sequence of event data is also constructed into directed acyclic graphs and through the use of a subgraph isomorphism algorithm we are able to detect specified patterns of events originating from a single cell. Two projects in the field of cancer research are here discussed that describe and validate the application of the event analysis programs. In the first project, mitotic catastrophe (MC) research [Ianzini and Mackey, 1997; Ianzini and Mackey, 1998; reviewed by Ianzini and Mackey, 2007] is enhanced with the addition of live cell imaging to traditional laboratory experiments. The event analysis program is used to describe the yield of normal or abnormal divisions, fusions, and cell death, and to detect patterns of reductive division and depolyploidization in cells undergoing radiation-induced MC. Additionally, the biochemical and molecular data used in conjunction with live cell imaging data are presented to illustrate the usefulness of combining biology and engineering techniques to elucidate pathways involved in cell survival under different detrimental cell conditions. The results show that the timing of depolyploidization in MC cells correlates with increased multipolar divisions, up-regulation of meiosis-specific genes, and the production of mononucleated cell progeny. It was confirmed that mononucleated cells are produced from multipolar divisions and these cells are capable of resuming normal divisions [Ianzini et al., 2009]. The implications for the induction of meiosis as a mechanism of survival after radiation treatment are discussed. In the second project, the effects of long-term fluorescence excitation light exposure are examined through measurements of cell division and cell death. In the field of live cell imaging, probably the most modern and most widely utilized technique is fluorescence detection for intracellular organelles, proteins, and molecules. While the technologies required to label and detect fluorescent molecules in a cell are well developed, they are not idealized for long term measurements as both the probes and excitation light are toxic to the cells [Wang and Nixon, 1978; Bradley and Sharkey, 1977]. From the event analysis data it was determined that fluorescence excitation light is toxic to multiple cell lines observed as the reduction of normal cell division, induction of cell death, and apparent morphological aberrations.
28
Ekroll, Ingvild Kinn. "Light induced cell death in the cancer cell line AY-27:Modes of cell death after red light hexaminolevulinate photodynamic therapy and effects of fractionated light delivery." Thesis, Norwegian University of Science and Technology, Department of Physics, 2009. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-6317.
Full text
29
Püschel, Franziska. "Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667909.
Full textAbstract:
Metabolic alterations in cancer cells are primarily caused by oncogenic mutations and cancer cells are more dependent on glucose compared to non-transformed tissue. Targeting the cancer metabolism opens up a new strategy for anti-cancer therapy. In order to make drugs more efficient and applicable in the clinic, it is necessary to fully investigate the cancer cell metabolism, especially of how cancer cells die upon glucose deprivation and more importantly, the consequences on the surrounding tissue when modifying or interfering with the metabolism.
The unfolded protein response (UPR) is an intracellular stress response which is induced upon glucose deprivation. The activation of the three branches of the UPR facilitates pro-survival responses, however, chronic exposure to intra- or extracellular stress results in a switch towards a pro-death UPR response. The UPR is also described to be involved in pro-inflammatory responses due to the induction of cytokines and chemokines in several cell lines. Therefore, the release of cytokines upon glucose deprivation could facilitate the infiltration or exclusion of immune cells.
We hypothesized that cancer cells die in an UPR dependent manner and that cancer cells release inflammatory cytokines upon glucose deprivation, which promote the infiltration of immune cells.
We found that HeLa cells exposed to glucose deprivation, died in a TRAIL receptor 1 (DR4) and 2 (DR5) dependent manner, which was mediated by the activation transcription factor 4 (ATF4).
Furthermore, we found the release of pro-tumorigenic cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and the leukemia inhibitory factor (LIF) from glucose deprived cancer cells as well as upon treatment with anti-metabolic drugs. We found that IL 6 and IL-8 but not LIF were regulated by ATF4 and p65 upon glucose deprivation. Moreover, the conditioned media of glucose deprived A549 promoted the migration of macrophage-like THP-1 cells as well as primary B cells and neutrophils isolated from human blood.
These findings are important, since interfering with the cancer metabolism by using anti metabolic drugs could suppress the anti-tumorigenic effect of these drugs by promote pro-tumorigenic responses.
30
Laane, Edward. "Cell death mechanisms of anti-cancer agents and treatment response in acute leukemia /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-854-1/.
Full text
31
Wei, Na, and 魏娜. "The function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B45898650.
Full text
32
Van, Danielle. "Determining the mechanism of double-stranded RNA-induced cell death in ovarian cancer." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/265.
Full textAbstract:
Ovarian cancer is the most lethal of all gynecological cancers. Current ovarian cancer drug regimens, including taxanes and platinum-based agents, are susceptible to chemoresistance necessitating the development of novel chemotherapeutics. Within tumors pathogen-derived ligands, such as dsRNA, can activate pattern recognition receptors (PRRs) that are capable of inducing apoptosis. In this dissertation we have found that in ovarian cancer cell lines (DOV-13, SKOV-3, CAOV-3, and OVCAR-3), dsRNA treatment alters cell survival. When treated with dsRNA, ovarian cancer cell lines and patient samples could be divided into two categories, responsive which undergo significant levels of apoptosis (CAOV-3 and OVCAR-3) or non-responsive which are unaffected (DOV-13 and SKOV-3). Following dsRNA treatment, dsRNA receptor expression levels increase in responsive cell lines and patient samples only. This suggests a potential role for dsRNA receptors as biomarkers to identify dsRNA-responsive patients. Detailed investigation of the mechanism by which cell lines succumb to or avoid dsRNA-induced cell death showed that in responsive cell lines, NF-kappaB, IFN-beta and caspase 3 activation occurred. Cell death was caspase and IFN-dependent. In non-responsive cell lines, increased c-IAP2 levels and RIP1 kinase ubiquitination occurred, as well as, an increase in basal level autophagy with dsRNA stimulation. However, individual blockade of these pathways did not restore dsRNA-induced apoptosis. In a non-responsive cell line, dsRNA enhanced the action of paclitaxel, carboplatin, and vorinostat through an as yet undetermined mechanism. In a responsive cell line, dsRNA produced a synergistic effect when combined with these drugs. These novel dual therapies, innate immune ligand plus cytotoxic agent, may find application in chemoresistant ovarian cancers.
33
Mrschtik, Michaela. "Characterisation of the role of DRAM-related TMEM150 proteins in cancer cell survival, cell death and autophagy." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7932/.
Full textAbstract:
Autophagy, a cellular recycling mechanism, and apoptosis, a regulated mode of cell death, are two fundamental cellular processes that contribute to carcinogenesis and tumour growth as well as treatment sensitivity and resistance. The protein encoded by DRAM1, a p53-responsive gene, has previously been described as an autophagy and apoptosis modulator downstream of p53 activation. Furthermore, a family of DRAM1-related proteins has been uncovered by in silico analysis. Of the 5 members of this protein family, only DRAM1 and DRAM-2 had previously been tested for their roles in cell death and autophagy. Much less was known about the remaining three DRAM-family members TMEM150A/B/C (termed DRAM-5/-3/-4 by us for ‘DRAM-related/associated member-5/-3/-4’) and their potential roles in autophagy, cell death or cell survival in cancer cells. In this project, we therefore aimed to test whether these DRAM-family proteins could modulate autophagy, cell death or cell survival in in vitro cancer cell line systems. We used both retroviral, constitutive overexpression systems and CRISPR/Cas9-mediated gene disruption systems to study the effect of TMEM150 overexpression or TMEM150 ablation on these processes. In summary, we found that none of the TMEM150 genes were induced by p53, but starvation conditions increased TMEM150A and C transcript levels in some conditions. Moderate changes in TMEM150 protein levels showed no dramatic effect on cell growth and survival. Of the three TMEM150 proteins, only TMEM150B affected autophagy, while TMEM150A and C did not modulate autophagic processes in any of the assays performed. Moreover, we show that TMEM150B overexpression can improve cellular survival under glucose deprived conditions, while none of the other DRAM-family proteins seems capable of doing so. Additionally, serum or amino acid starvation did not show parallel effects. Lastly, we show that the influence of TMEM150B on autophagic processes is uncoupled from its ability to modulate survival in glucose-starved cells. Taken all together, with this work we provide an initial characterisation of the TMEM150 proteins, which may lay a foundation for future, expanded studies on the cellular functions of the DRAM-family.
34
Dächert, Jasmin Verfasser], Volker [Gutachter] Dötsch, and Simone [Gutachter] [Fulda. "Oxidative stress-induced cell death in paediatric cancer cell lines / Jasmin Dächert ; Gutachter: Volker Dötsch, Simone Fulda." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2018. http://d-nb.info/1176154664/34.
Full text
35
Dächert, Jasmin [Verfasser], Volker Gutachter] Dötsch, and Simone [Gutachter] [Fulda. "Oxidative stress-induced cell death in paediatric cancer cell lines / Jasmin Dächert ; Gutachter: Volker Dötsch, Simone Fulda." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2018. http://d-nb.info/1176154664/34.
Full text
36
Abdulkareem, Zana Azeez. "SK potassium and TRPM7 ion channel role in CNS cell survival and breast cancer cell death decisions." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/80343/.
Full textAbstract:
Cell survival is modulated by a cocktail of ion channels engaging cell life and death decisions through controlling key cellular messages such as apoptosis and proliferation. Unnatural regulation of these processes results in various disorders, for example neurodegenerative diseases, as well as the cancers. Nowadays, these pathologies are affecting millions of people per year in the world. Potassium (K+) ion channels appear to play a potent role in such illnesses since they can control many cellular gates in cell physiology such as ionic homeostasis and signalling cascades. Amongst the K+ channels, small (SK1-3) and intermediate (SK4) conductance Ca2+-activated potassium ion channels have recently been shown to save cells, thereby protecting mitochondrial function which serves as a cell survival platform. In the case of other ion channels, for instance transient receptor potential melastatin 7 (TRPM7), it is also repeatedly stated that such membrane channels shows an impressive and differential role in excitable and non-excitable cell survival. This channel also modulates ionic homeostasis of crucial ions in cellular physiology such as Ca2+. This study reveals that central nervous system (CNS) and breast cancer cells differentially express SK1-4 ion channel subtypes, and their functional presence is pharmacologically confirmed, however, in most cases these results were further clarified through small interference RNA (siRNA) method. Similarly, functional TRPM7 channel expression in CNS cells is also confirmed. In the CNS, SK1-4 channel activation rescues neurons from oxidative stress, whereas, TRPM7 channel inhibition protects CNS cells from this hydrogen peroxide (H2O2) harmful effect, as well as hypoxia and apoptosis, so improving cell survival. Excitingly, SK1-4 channels differentially exist between wild-type and Huntington’s affected mouse striatal cells, where diseased cells lack SK1-3 channels, key players in action potential activity. Interestingly, SK2 or SK3 channel subtypes are also functionally expressed in breast cancer cells with various phenotypes. This study established that these ion channels are powerful agents in a survival role, in fact controlling growth through cross-talk with an apoptotic avenue “intrinsic pathway”. SK2 or SK3 channel activation enhances cell viability, while its inhibition dampens cell growth. It is very noteworthy that SK2 and SK3 channels are not expressed in non-tumorigenic breast cells. In brief, SK1-4 and TRPM7 molecules are clearly implicated in the survival of diverse cell types through an apoptotic route, indicating that these ionic regulators are promising targets in channelopathies related to cellular degeneration and growth.
37
Pirzado, Muhammad Suleman. "Investigating cell senescence in basal cell carcinoma." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8633.
Full textAbstract:
The Aim of the project was to investigate cell senescence in basal cell carcinoma (BCC). Although the concept of oncogene-induced senescence (OIS) was originally confined to cultured cells, it is now well established that this mechanism has an important role in tumour biology. OIS represents a physiological response that restricts the progression of benign tumours into their malignant counterparts e.g. nevi to melanoma or adenoma to adenocarcinoma. Full malignancy is associated with the loss of important tumour suppressor genes including RETINOBLASTOMA and/or TP53. BCC of the skin is the most common skin tumour and is associated with mutational inactivation of the PTCH1 tumour suppressor gene (and less frequently oncogenic activation of SMOOTHENED). Although BCC does not appear to stem from precursor lesions - though mouse models of BCC display areas of basaloid hyperproliferation - and it is relatively stable at the genomic level, we sought to determine if these unique tumours display any characteristics of OIS. Human BCCs were positive for Senescence-associated β-galactosidase (SA-β-gal) activity (pH 6.0) and expressed known markers of senescence including DCR2, DEC1 (SHARP2) as well as the cell cycle inhibitors p15INK4b and p16INK4a. Interestingly, SA-β-gal activity was observed in stromal cells surrounding the tumour islands and this may account for why BCCs are difficult to culture in vitro as senescent cells are known to express increased levels of growth factors, cytokines and ECM proteins. To determine if OIS is associated with Hedgehog signalling in BCC, I employed a novel in vitro model of BCC created through PTCH1 suppression in human immortalised NEB1 keratinocytes. NEB1-shPTCH1 cells are viable and proliferative (albeit more slowly than control NEB1-shCON cells) and do not display SA-β-gal activity but they express higher levels of several senescent markers including DCR2 and p21WAF1. I also investigated senescence in a Mouse model of BCC in which one allele of Ptch1 is mutated and which on x-ray irradiation results in BCC formation. The expression of known markers of senescence including DCR2, DEC1 (SHARP2) as well as the cell cycle inhibitors p15INK4b, p16INK4a and p53 were all with the exception of p21WAF1 detected in these tumours. Together these data suggest that senescence is a characteristic of BCC and may explain why these tumours rarely metastasise.
38
Gill, Zahidah Perveen. "Modulation of cellular survival by insulin-like growth factor binding protein-3." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297809.
Full text
39
Button, Robert William. "Characterising futile autophagosome based toxicity and its implications in disease." Thesis, University of Plymouth, 2017. http://hdl.handle.net/10026.1/10381.
Full textAbstract:
Macroautophagy (‘autophagy’ hereafter) mediates the capture of aberrant cytoplasmic material into vesicles called autophagosomes, which then shuttle to lysosomes for degradation. Autophagy is implicated in numerous diseases, largely in a pro-survival role. However, autophagy has also been suggested as a form of programmed cell death (PCD), from cases of dying cells showing autophagosome accumulations. Debate occurs between whether these vesicles drive the lethality, or are instead a failing rescue attempt. This study aimed to provide clarity on this issue. Via the use of chemical and genetic strategies of inducing autophagosome accumulations, we found combining stimulators of autophagosome biogenesis with lysosomal degradation inhibitors gave rise to toxicity. Notably, this effect was dependent on the autophagy machinery and independent of other PCD routes. Research into the underlying mechanisms revealed an energy deficit under these conditions. Since autophagosomes cannot be recycled at lysosomes here, their continued synthesis affords no survival benefits, and instead just serves to deplete cellular energy further. For this reason, we designate this event ‘Futile Autophagosome Synthesis’ (FAS) toxicity. Other contributors to this toxicity include the persistence of harmful agents like Reactive Oxygen Species (ROS). Having established our FAS model, we explored its relevance in both cancer and neurodegeneration. Importantly, we found FAS inducing strategies to be effective in tumour treatment. Also, inhibiting FAS reduced the toxicity seen in neurodegenerative disease. Therefore, not only does this study improve our knowledge of autophagy in PCD, but also indicates it may have important medical implications.
40
Oberdanner, Christian. "ROS and antioxidant systems in apoptosis oxidant balance in cell death and cancer therapy." Saarbrücken VDM Verlag Dr. Müller, 2007. http://d-nb.info/988931672/04.
Full text
41
Bagdasarian, Arine. "Cancer Therapy : - The mitochondrial Bcl-2 protein familyas drug targets for inducing cell death." Thesis, Umeå universitet, Kemiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-102018.
Full text
42
Emich, Helena. "Clinical implications of cancer stem cell properties in oral squamous cell carcinoma." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8479.
Full textAbstract:
CD44 has been described as a marker of cancer stem cells in oral squamous cell carcinoma (OSCC). The main objective of this study was to characterise expression of CD44 in both fresh samples of human OSCC and in cell lines generated from them, and to examine its correlation with selected clinicopathological parameters of the tumours of origin. The epithelial fraction in 20 fresh OSCC samples was identified by the standard method using the negative selection technique with antibodies against non-tumour cells. A novel method of identifying the epithelial fraction, termed positive selection, was also developed and used for analysis of 14 additional OSCC samples. This new method, using epithelial-specific antibodies, led to a considerable improvement in the efficiency and the accuracy of the procedure. The frequency of CD44+ cells in the epithelial fraction of the tumour specimens was assessed by FACS and varied widely (3-97%). High frequency of CD44+ cells in tumour samples was found to be associated with high tumour grade, discohesive invasion front and presence of lymph node metastases (p<0.01, as calculated with Spearman’s ranked test and Fisher’s exact test). It was also observed, that the percentage of CD44+ cells changes when cells isolated from tumour samples are propagated in culture. Nearly all cells in cell lines generated from OSCC samples showed CD44 expression when analysed by FACS. However, a markedly higher level of CD44 expression (as assessed by median fluorescence intensity for cell surface CD44) was found for early passage cell lines generated from metastatic OSCC and lymph node metastases as compared to cell lines generated from nonmetastatic OSCC. These findings show that a high frequency of CD44+ cells in fresh OSCC tissue and a high level of CD44 expression in cultured OSCC cells correlate 11 with more aggressive tumour behaviour. These results might provide important information of prognostic and therapeutic value.
43
Du, Shengnan. "Novel Microtubule-Disrupting Indole-Based Chalcones That Induce Cell Death in Glioblastoma." University of Toledo Health Science Campus / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1513072908428639.
Full text
44
Lawton, R. L. "Cytotoxic T cell activation in the mouse." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278527.
Full text
45
Martinsson, Petra. "Pharmacological Studies of CHS 828 and Etoposide Induced Tumour Cell Death." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1500.
Full textAbstract:
Antitumour properties of the cyanoguanidine CHS 828 and analogues were discovered in 1997. CHS 828 is presently in clinical phase I/II trials. This thesis encompasses in vitro studies of the kinetics and mode of cell death induced in the human cell line U-937 GTB, by CHS 828 and the standard antitumour drug etoposide.
Etoposide induces apoptosis in U-937 GTB within 4 h. The cells exhibited apoptotic morphology, including condensed and fragmented nuclei and formation of apoptotic bodies, activation of caspase 3 and 8, and DNA fragmentation, visualised by TdT-mediated dUTP nick end-labelling (TUNEL).
CHS 828 induced few and weak signs of apoptosis. Metabolic activity was the only parameter affected during the first 24 h of exposure. After ~30 h, proliferation (DNA synthesis) and protein synthesis ceased, and viability started to decrease towards 10% at 72 h. Morphology and ultrastructure of dying/dead cells showed predominant necrosis. The decrease in viability was postponed by protein synthesis inhibition or maintenance of ATP levels by 3-aminobenzamide. In addition, 3-aminobenzamide switched morphology towards apoptosis.
Continuous co-exposure to CHS 828 and etoposide resulted in impressive cell kill synergy in U-937 GTB cells at effect levels of 30-70%. Pre-exposure to CHS 828 for 18 h or more, on the other hand, resulted in diminished cell kill and inability to activate the apoptotic machinery upon etoposide stimulation, evaluated by morphology and caspase activity.
In summary, CHS 828 induced cell death is predominantly non-apoptotic, does not involve caspases and can be postponed by maintained protein synthesis and ATP levels.
46
Senaratne, Siddhika Gaurie. "Action and interaction of various drugs with signal transduction pathways, leading to cancer cell death." Thesis, St George's, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398083.
Full text
47
Dunn, Catherine Ann. "Transcriptional regulation and cell transformation by v-Jun." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390777.
Full text
48
Lucas, Mark. "Modulation of apoptosis by HSP72 in human myeloid leukaemia and endothelial cells." Thesis, University of Warwick, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343124.
Full text
49
Checkett, Jane Melinda. "Development of a micro-scale microtransfection technique exploiting reporter gene systems to analyse bcl-2 family promoter activity." Thesis, Keele University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325826.
Full text
50
Daly, Maria Catherine. "Chromosome 3 deletion mapping in human small cell lung cancer." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304095.
Full text