Дисертації з теми "Autophagy inhibitors"
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Zha, Beth Shoshana. "HIV Protease Inhibitors Trigger Lipid Metabolism Dysregulation Through Endoplasmic Reticulum Stress and Autophagy." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/273.
Повний текст джерелаKhan, Omar Ali. "HR23B, a biomarker for HDAC inhibitors." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e.
Повний текст джерелаMartin, Mackenzie. "Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6314.
Повний текст джерелаTimme, Cindy R. "Drug Resistance Mechanisms to Gamma-secretase Inhibitors in Human Colon Cancer Cells." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4954.
Повний текст джерелаRobke, Lucas [Verfasser], Herbert [Akademischer Betreuer] Waldmann, and Martin [Gutachter] Engelhard. "Discovery and target identification of small molecule autophagy inhibitors / Lucas Robke ; Gutachter: Martin Engelhard ; Betreuer: Herbert Waldmann." Dortmund : Universitätsbibliothek Dortmund, 2017. http://d-nb.info/1139892592/34.
Повний текст джерелаRummelt, Marjorie A. [Verfasser], Herbert [Akademischer Betreuer] Waldmann, and Martin [Gutachter] Engelhard. "Identification and biological characterization of indoline-based autophagy inhibitors / Marjorie A. Rummelt ; Gutachter: Martin Engelhard ; Betreuer: Herbert Waldmann." Dortmund : Universitätsbibliothek Dortmund, 2017. http://d-nb.info/113989255X/34.
Повний текст джерелаPeng, Luo-Gen [Verfasser]. "Urokinase-type plasminogen activator receptor contributes to chemosensitivity and epithelial-to-mesenchymal transition in PDAC : uPAR and p38 regulate autophagy dependent gemcitabine resistance in AsPC1: autophagy inhibitors and gemcitabine as a potential combined therapy for a subgroup of pancreastic cancers / Luogen Peng." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1221802313/34.
Повний текст джерелаPeng, Luogen [Verfasser]. "Urokinase-type plasminogen activator receptor contributes to chemosensitivity and epithelial-to-mesenchymal transition in PDAC : uPAR and p38 regulate autophagy dependent gemcitabine resistance in AsPC1: autophagy inhibitors and gemcitabine as a potential combined therapy for a subgroup of pancreastic cancers / Luogen Peng." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1221802313/34.
Повний текст джерелаGarivet, Guillaume [Verfasser], Herbert [Akademischer Betreuer] Waldmann, and Alfred [Gutachter] Wittinghofer. "Small molecule inhibition of lipidated proteins/cargo interaction and synthesis of a cinchona alkaloid-derived library as potent autophagy inhibitors / Guillaume Garivet ; Gutachter: Alfred Wittinghofer ; Betreuer: Herbert Waldmann." Dortmund : Universitätsbibliothek Dortmund, 2017. http://d-nb.info/1149920424/34.
Повний текст джерелаMeza, Daniel. "Sphingosine Kinase 1 Inhibitor, A Novel Inducer of Autophagy." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1871.
Повний текст джерелаSahin, Katherine B. "Evaluation of cell division cycle associated protein 3 (CDCA3) as a novel prognostic/therapeutic target for EGFR-mutant non-small cell lung cancer." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/231468/1/Katherine_Sahin_Thesis.pdf.
Повний текст джерелаDrullion, Claire. "Réponse et résistance aux inhibiteurs de tyrosine kinases dans le modèle de la LMC : identification et régulation des morts cellulaires." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21872/document.
Повний текст джерелаChronic Myeloid Leukemia is a myeloproliferative syndrome connected to the acquisition of a chromosomal abnormality t(9;22) leading to the expression of a fusion protein p210 Bcr-Abl of whom the tyrosine kinase activity deregulated is necessary and sufficient to engender the disease.This pathology benefits since 2002 of a therapeutic advance: the tyrosine kinase inhibitors (TKI). This targeted therapeutics, from which imatinib is the front-line, is very effective because 80 % of patients enters in remission. However, 20 % of the treated patients develop primary or secondary resistances which can be dependent or not to the Bcr-Abl oncogene among which some have been characterized. Indeed, CML is now a model to study both oncogenic and resistances mechanisms.Resistance to TKI in CML can be considered on two sides. On one hand the resistance allowing the leukemic cell to escape the therapeutic pressure of TKI and on a second hand the “intrinsic” resistance of Leukemic stem cells by multiple mechanisms. This second level of resistance is at the origin of the CML recurrence.This thesis consisted in determining how could die the CML cells in response to TKI to bring to light cell deaths induced and the regulations existing between them. Furthermore, it allowed exploring the use of non-apoptotic cell deaths to overcome resistance to TKI.We showed for the first time by using CML cell lines (K562, Lama-84 and AR-230), that imatinib (as well as nilotinib and dasatinib) induced senescence besides an apoptotic response. In absence of apoptosis, by its inhibition, senescence becomes a major response of CML cells suggesting that apoptosis is limiting senescence. Autophagy activated by TKI negatively regulates apoptosis while it is necessary for a major senescent response. We were able to bring to light two types of senescence in response to TKI : a senescence dependent and a senescence independent of autophagy suggesting it plays a critical role in cell death regulation.Because CML cells can die by non-apoptotic cell deaths, we used them to eliminate TKI resistant cells. Mycophenolic acid (MPA), an immonusuppressor already used in therapeutic as an immunosuppressive agent has been extensively used. MPA by inhibiting the synthesis of GTP induces DNA damage and apoptotic and\or senescent response. In this context, autophagy protects the cells from apoptotic response but do not from senescence. Conversely, MPA is a powerful inductor of apoptosis on hematopoietic primary cells. Indeed, it induces apoptosis of TKI resistant primary cells whatever the mechanism involved (overexpression of tyrosine kinases or mutation of Bcr-Abl). MPA illustrates the need to look for new molecules to eliminate TKI resistant CML cells, particularly when patients are in the evolved blastic phase of the disease.These results suggest that senescence is one of the deaths which can be used to overcome resistance of cancer cells
Gallagher, Laura. "Nutrient-dependent effects of the autophagy-lysosomal inhibitor, Chloroquine, on cell death and lysosomal functionality." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27858.
Повний текст джерелаSingh, Subir. "Role of cytochrome P450 in breast carcinogenesis." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/role-of-cytochrome-p450-in-breast-carcinogenesis(ed2c5c1b-d2e9-458b-acc5-3c320cf22ee6).html.
Повний текст джерелаWatanabe, Motonobu. "Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation." Kyoto University, 2009. http://hdl.handle.net/2433/124304.
Повний текст джерелаHannigan, Adrienne Michelle. "Investigating the role of the inhibitor of apoptosis protein, Apollon, in the regulation of autophagy in breast cancer cells." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/26673.
Повний текст джерелаEimer, Sandrine. "Etude des réponses induites par l’erlotinib dans des cellules de lignées de glioblastome." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21822/document.
Повний текст джерелаGlioblastoma (GBM) is the most common primary central nervous system tumor in adults and the prognosis remains dismal, any treatment used. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in GBM, making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. We showed for U87-MG and DBTRG-05MG, two human GBM cell lines, that erlotinib can’t trigger apoptosis, related either to accumulation of αB-crystallin capable to impair caspase 3 cleavage, or to constitutive deficit for procaspase 3 in DBTRG-05MG. Apoptosis deficit switches the cell to autophagic process. Inhibition of autophagy with RNA interference or chloroquine resulted in sensitization of U87 and allowed a synergistic effect with erlotinib at therapeutic doses.Moreover, GBM showed a heterogeneous cell composition with cancer stem cells, progenitors and more differentiated cells. In this study, we test erlotinib in vitro on other GBM models: three cell lines established from surgically resected GBM specimens, grown along two features adherent and neurospheres. On the three differentiated adhering cell lines, erlotinib had only a moderate activity. Conversely, on neurosphere forming cell lines, erlotinib induced a strong inhibition of cell growth related to the EGFR amplification and EGFR expression. A short erlotinib exposure induced cell death primarily in nestin-positive cells; however it was found without effect on neurosphere initiating activity and self renewal. These results suggest that EGFR pathway activation is essential for the proliferation of GBM progenitor cells but dispensable for stem-like cancer cells self–renewal. As Hedgehog pathway is known to be activated in neural stem cells, we assayed the Hedgehog pathway inhibitor cyclopamine in association with erlotinib. While each drug separately was without effect on sphere initiation, their combination led to a 25 fold decrease in the sphere number (p=0.0004).These in vitro models are convenient to investigate resistance mechanisms in GBM. Furthermore, they focus on the necessity to exploit drug combinations for greatest efficiency
Xie, Wei. "Transcription Inhibitor Lurbinectedin and Oncolytic Peptide LTX-401 trigger Immunogenic Cell Death and Synergize With Immune Checkpoint Blockade Lurbinectedin Synergizes With Immune Checkpoint Blockade To Generate Anticancer Immunity Tumor Lysis With LTX-401 Creates Anticancer Immunity Autophagy Induction by Thiostrepton Improves the Efficacy of Immunogenic Chemotherapy Oncolysis With DTT-205 and DTT-304 Generates Immunological Memory in Cured Animals." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL072.
Повний текст джерелаCancer is the second leading cause of death worldwide, despite the existence of standard treatment, innovative therapeutic strategies and drugs are still in urgent demand. The combination of immunogenic cell death (ICD) inducing drugs and immune checkpoint blockade (ICB) seems to be a promising modality. In this thesis, we demonstrated Lurbinectedin, a transcription inhibitor newly approved for relapsed lung cancer treatment, triggers hallmarks of ICD in four different human and murine cell lines in vitro. Vaccinated with Lurbinectedin-treated fibrosarcoma cell protects immunocompetent mice from rechallenge with syngeneic tumours. Lurbinectedin restrains transplanted fibrosarcoma growth in an immune dependent manner. Both transplanted MCA205 cancer and hormone/carcinogen induced breast cancer were sensitized by Lurbinectedin to PD-1 and CTLA-4 double ICBs. Of note, long-term immunological memory was generated in cured mice. Further, we evaluated the anticancer capacity of LTX-401, an oncolytic peptide designed for local immunotherapy. Sequential intratumoral injections of LTX-401 dramatically retards subcutaneous MCA205 and TC-1 tumour growth in immunocompetent host, yet shows limited therapeutic effect of anti-CTLA-4 or anti-PD-1/anti-CTLA-4 ICBs. Moreover, sequential LTX-401 treatment with double ICBs exhibits systemic antitumor immunity to both treated and abscopal tumour. In conclusion, lurbinectedin and LTX-401 induce cancer cell immunogenic cell death and enhance the anticancer effects of immune chekcpoint blockade. These results lay the experimental foundation of combination regiments and may facilitate the clinical trial design
Aubert, Serge. "Effets multiples du glycérol sur le métabolisme de la cellule végétale non chlorophyllienne." Université Joseph Fourier (Grenoble), 1994. http://www.theses.fr/1994GRE10217.
Повний текст джерелаDias, Pedro Gonçalo Guedes. "Modulation of neuronal mitochondrial dynamics, autophagy and huntingtin proteostasis by HDAC inhibitors: Insights for Huntington's disease." Doctoral thesis, 2015. https://repositorio-aberto.up.pt/handle/10216/78858.
Повний текст джерелаDias, Pedro Gonçalo Guedes. "Modulation of neuronal mitochondrial dynamics, autophagy and huntingtin proteostasis by HDAC inhibitors: Insights for Huntington's disease." Tese, 2015. https://repositorio-aberto.up.pt/handle/10216/78858.
Повний текст джерелаHerbert, James Taylor. "The Role of Autophagy and Translation Initiation Factors in Overcoming Resistance to mTOR Inhibitors in Prostate Cancer." Diss., 2013. http://hdl.handle.net/10161/7097.
Повний текст джерелаCastration resistant prostate cancer (CRPC) causes significant morbidity and mortality around the world and improving treatment options for patients with CRPC is a major concern for biomedical research. Because of the importance of activating mutations in the PI3K/AKT/mTOR pathway in prostate cancer, several mTOR inhibitors have been tested for efficacy in CRPC but despite promising preclinical findings, the results of clinical trials have been disappointing. The findings of several groups, including a clinical trial of RAD001 conducted at Duke, suggest that feedback upregulation of PI3K and autophagy may be potential mechanisms for resistance of CRPC to mTOR inhibitor therapy.
The main goal of this dissertation was to explore these mechanisms in vitro and to determine if combinations of PI3K inhibitors and different classes of mTOR inhibitors can overcome resistance to mTOR inhibitor monotherapy. In particular, we used immunoblotting, reverse phase protein microarrays, polysome profile analysis, cell cycle analysis, and several techniques for determining cell survival and proliferation to explore the differences in survival, proliferation, autophagy, and activity of the AKT, translation initiation, and autophagy cell signaling networks between prostate cancer cell lines treated with different combinations of mTOR and PI3K inhibitors. Our findings revealed that the combination of PI3K and mTOR inhibition leads to a synergistic inhibition of prostate cancer cell survival and cytostasis that is correlated decreased translation rates, hypophosphorylation of 4E-BP1, autophagy, and an uncoupling of normal signaling between AKT and mTOR. We were able produce an effect on cell survival similar to treatment with high doses of mTOR/PI3K inhibitor combinations by inhibiting cap-dependent translation using a non-phosphorylatable mutant of 4E-BP1. In contrast, knocking down two major autophagy genes had little to no effect on the survival of prostate cancer cells treated with PI3K/mTOR inhibitors but did protect from cell death caused by the UPR activator tunicamycin.
We conclude that treatment strategies that target PI3K, mTORC1 and mTORC2 simultaneously have the potential to be clinically useful in CRPC, probably due to the increased inhibition of eIF4E activity and cap-dependent translation when compared to monotherapy with allosteric mTORC1 inhibitors. Although autophagic cell death can be induced in prostate cancer cells, the autophagy observed after inhibition of PI3K and mTOR does not appear to contribute to cell death and is not a major resistance mechanism under these conditions. Nevertheless, we did observe different roles for autophagy in the survival of cells exposed to different types of stressors, and further elucidation of autophagy signaling networks may yet provide useful clinical targets.
Dissertation
Kolárik, Matúš. "Studium působení tyrosinkinasových inhibitorů a jejich metabolitů na buněčné linie nádorů." Master's thesis, 2021. http://www.nusl.cz/ntk/nusl-448743.
Повний текст джерелаGooskens, Brigite Teixeira Ribeiro Van Den Wildenberg. "Stents, statins and sirolimus: a new approach to prevent restenosis." Master's thesis, 2018. http://hdl.handle.net/10316/81998.
Повний текст джерелаIntrodução: As doenças cardiovasculares continuam a ser a principal causa de morte no mundo, sendo a doença arterial coronária, responsável por 20%, anualmente, na Europa. O tratamento abrange abordagem conservadora, revascularização miocárdica cirúrgica e intervenção coronária percutânea, muito menos invasiva. Os stents farmacológicos implantados pela intervenção coronária percutânea foram um marco que reduziu significativamente a taxa de reestenose do stent e a trombose do stent associada aos primeiros stents metálicos usados; no entanto, os stents farmacológicos ainda apresentam algumas desvantagens. Além da inibição da proliferação das células musculares lisas, a completa reendotelização do vaso lesado após o implante do stent, com endotélio regenerado, mostrando características e funções morfológicas normais, é um objetivo estratégico para o stent. Uma grande desvantagem do uso de stents farmacológicos com compostos como a rapamicina (sirolimus), um inibidor do mTOR, é que não apenas atua nas células musculares lisas vasculares, mas também nas células endoteliais, o que poderá exacerbar a disfunção endotelial provocada pelo stent. Embora a autofagia possa ser ativada diretamente pela inibição da mTOR, ela pode ser ativada indiretamente, através da proteína quinase ativada por 5 ' monofosfato de adenosina (AMPK). Como as estatinas podem ativar a AMPK e melhorar a função endotelial, reduzindo a inflamação, nós colocamos a hipótese que as estatinas possam reduzir os efeitos deletérios dos stents farmacológicos de sirolimus, nas células endoteliais, melhorando a resposta arterial e reduzindo a taxa de reestenose.Métodos: Para abordar esta questão, utilizámos uma abordagem celular, com uma linhagem celular endotelial cardíaca imortalizada de ratos e uma cultura primária de células endoteliais. Estas células foram tratadas com estatinas (sinvastatina) ou rapamicina separadamente ou em combinação. Em seguida, avaliou-se a atividade endotelial por ensaio de tubulação de matrigel, ensaios de migração e fluxo de autofagia/atividade por western blot.Resultados: Os nossos resultados demonstraram que, quando em combinação com a rapamicina (ou sirolimus), a sinvastatina reverte parcialmente os efeitos negativos da rapamicina no potencial angiogénico das células endoteliais, observado por um aumento na capacidade de migração e tubulação. Além disso, observámos que a sinvastatina promoveu a autofagia.Discussão: O aumento da angiogénese pode ser atribuído a um aumento de neovasos de paredes finas e frágeis, que podem servir para o recrutamento de leucócitos para áreas de alto risco da placa. Por outro lado, a capacidade das células endoteliais para a angiogénese correlaciona-se com uma resposta arterial adequada e um endotélio funcional. Observou-se ainda um aumento da capacidade de migração das células endoteliais, o que significa que elas responderam a um estímulo quimiotácito e migraram através de uma barreira física em direção a ele, o que é desejável quando há lesão endotelial, nomeadamente aquela induzida pela impantação de um stent.Os resultados sugerem que comparando com a rapamicina, a adição de sinvastatina promove a autofagia, que tem sido associada à angiogénese nas células endoteliais, com melhor resposta arterial. Conclusão: Estes resultados abrirão caminho para novos entendimentos sobre os efeitos das estatinas nas células vasculares, e potencialmente um stent com eluição de estatina, o padrão na prática clínica, para um menor risco de reestenose e disfunção endotelial.
Introduction: Cardiovascular diseases remain the leading cause of death worldwide, being coronary artery disease accountable for up to 20% annually in Europe. The treatment encompasses conservative management, coronary artery bypass graft and the much less invasive percutaneous coronary intervention. The drug-eluting stents deployed by percutaneous coronary intervention were a milestone that significantly reduced the stent restenosis rate and stent thrombosis associated to the first-ever used bare-metal stents; however, drug-eluting stents still present some drawbacks. Besides smooth-muscle cells proliferation inhibition, achieving complete reendothelialization of injured vessel after stenting, with a regenerated endothelium showing normal morphologic characteristics and functions, is a strategic objective for a stent. One major disadvantage of the use of drug-eluting stents with compounds such as rapamycin, also known as sirolimus, a mTOR inhibitor, is that not only acts on the vascular smooth muscle cells, but also on endothelial cells, which might exacerbate the endothelial function impairment when the stent is deployed. Although autophagy can be directly activated by mTOR inhibition, it can be activated indirectly, namely through 5’ adenosine monophosphate-activated protein kinase (AMPK). Since statins can activate AMPK and improve endothelial function, reducing inflammation, we hypothesize that statins can reduce the detrimental effects of sirolimus-eluting-stents on endothelial cells promoting a beneficial increase in endothelial function and consequentially a better arterial healing response, and reduced stent restenosis.Methods: To address this question, we used a cell-based approach, with an immortalized mouse cardiac endothelial cell line and an endothelial cell primary culture. These cells were treated with statins (simvastatin) or rapamycin separately or in combination. Afterwards we evaluated endothelial activity by matrigel tubulation assay, migration assays and autophagy flux/activity by western blot. Results: Our results demonstrated that when in combination with rapamycin (or sirolimus), simvastatin partially reverts the negative effects of rapamycin in the endothelial cells angiogenic potential, observed by an increased tubulation and migration capacity. Moreover, we observed that simvastatin potentiates autophagy regulation.Discussion: The increase on angiogenesis might be attributable to an increase of thin-walled and fragile neovessels that may serve as a pathway for recruitment of leukocytes to high-risk areas of the plaque. On the other hand, the capacity of endothelial cells for angiogenesis correlates with a proper arterial healing response and functional endothelium. There was an increase of the ability of endothelial cells to migrate and subsequently close a wound, what means that they were able to follow chemo-attractant and migrate through a physical barrier toward it, which is a desirable quality when there is endothelial damage, such as when a stent is deployed.Comparing to rapamycin alone, the addition of simvastatin seems to further increase autophagy, that has been associated with angiogenesis in endothelial cells, and with a better arterial healing response. Conclusion: These results will pave the way for new understandings on the effects of statins on the vascular cells, and potentially a statin-eluting stent the default one on clinical practice, for a lower risk of restenosis and endothelial dysfunction.
Yu-WeiChiu and 邱宥維. "B1 as an autophagy inhibitor effect on RGNNV replication and host AMPK autophagy signaling pathway." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/rb4432.
Повний текст джерелаChen, Man-Chin, and 陳曼菁. "Connexin 43 inhibits tumor growth by inducing autophagy." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/9ydu8z.
Повний текст джерела中國醫藥大學
基礎醫學研究所碩士班
102
Autophagy is a cellular process that mediates the degradation of long-lived proteins and unwanted organelles in the cytosol. Tumor cells frequently display lower levels of basal autophagic activity than their normal counterparts and fail to increase autophagic activity in response to stresses. Directly cell-to-cell communication is critical for maintaining homeostasis. Thus, the regulation of connexin protein levels is important. Gap junction channels are composed of connexons (or hemichannels) which are comprised of integral four-pass trans-membrane protein called connexins. Connexin 43 (Cx43) is the most extensively expressed in many cell types. The degradation mechanisms for connexins have been demonstrated in autophagosomal degradation pathway. The presence of functional gap junctions is highly relevant for autophagy. Here, we decreased Cx43 expression by short-hairpin RNA technology and examined their activities in murine cancer cells with serum starvation status. The autophagic markers were decreased after tumor cell downregulated Cx43. The loss of Cx43 expression decreased autophagy, which displays lower levels of basal autophagic activity in a majority of cancers. To study the pathway underlying Cx43-induced effects, we found that Cx43 induced a significant increase in mitogen-activated protein kinases (MAPK) signal pathways which involved in autophagy. Herein, our findings that Cx43 in controlling tumor growth may induce autophagic signal pathways.
Lai, Wei-Ting, and 賴瑋婷. "Connective Tissue Growth Factor inhibits Cancer Metabolism and Autophagy." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/5hpr97.
Повний текст джерела國立臺灣大學
臨床牙醫學研究所
105
In Taiwan, oral cancer (in particular oral squamous cell carcinoma, OSCC) is the fourth leading cause of death in males, and is one of the causes with high death rate worldwide. In this study, we seek to uncover the underlying mechanism of OSCC and help the development of new therapeutic strategies for OSCC. First, we analyzed 82 OSCC cases and confirmed that OSCC patients with high ataxia telangiectasia mutated interactor (ATMIN) expression showed poor differentiation, higher TNM stages, greater lymph-node metastasis, and shorter accumulated survival time. Evidence from a buccal orthotopic implantation mouse model showed that silencing of ATMIN expression reduced lymph node metastasis and prolongs the survival of mice. ATMIN is now considered as a poor prognosis biomarker, and our study results help to identify possible therapeutic targets of downstream genes for designing effective therapeutic strategies for OSCC. Second, my previous studies showed that connective tissue growth factor (CTGF/CCN2) significantly blocked glycolysis, mitochondrial oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production. Moreover, CTGF showed no effects in normal bronchial and oral epithelial cells. We demonstrated that CTGF decreased glycolysis, mitochondrial oxidative phosphorylation, ATP generation and mitochondrial DNA (mtDNA) copy number by increasing the degradation of mitochondrial transcription factor A (mtTFA) through ubiquitin proteasome pathway and in turn reduced migration and invasion of OSCC cells. Autophagy can promote cancer cell survival or resistance under conditions of poor nutrient supply, chemotherapy or target therapy. In this study, we demonstrated that CTGF inhibited late stage autophagy through blocking autophagosome-lysosome fusion under starvation condition. We further showed that cotreatment of CTGF could markedly enhance the therapeutic efficiency of Erbitux in vivo Finally, we showed that overexpression of CTGF significantly decreased Rab5A expression, which is essential for completion of autophagy. Furthermore, expression of a wild type or constitutive active form of Rab5A could restore CTGF-inhibited autophagy flux. We investigated the clinical importance of CTGF-Rab5A axis in OSCC patients, the results showed that high Rab5A mRNA expression was significantly associated with an advanced clinical pathological TNM stage. A reverse correlation between CTGF and Rab5A was also demonstrated. The findings in this study demonstrated that ATMIN and Rab5A can be poor prognostic biomarkers in OSCC. I believe that CTGF has the potential to be developed as an additive therapeutic agent for cancer treatment in the future.
Hsieh, Shang-Ying, and 謝尚穎. "Development of a Novel Quinoline-Based Autophagy Inhibitor for Effective Cancer Treatment." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/58qd94.
Повний текст джерелаChiao, Ming-Tsang, and 矯明昌. "The Mechanism of Autophagy Induced by Histone Deacetylase Inhibitor (SAHA) in Glioblastoma Stem Cell." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/64775778137449422385.
Повний текст джерела中山醫學大學
醫學研究所
101
We report that glioblastoma stem-like cells (GSCs) can form vasculogenic mimicry in tumor xenografts and express pro-vascular molecules. We isolated GSCs from resected human glioblastoma tissues and demonstrated their stemness, differentiation, and in vivo tumor-initiating potential. Through a limiting dilution assay, CD133+ (CD133+-GSC) and CD133- (CD133--GSC) subpopulation of GSCs were obtained. Orthotopic xenotransplantation study revealed that these two subpopulations of GSCs shared similar efficacy in tumor formation but showed distinct intratumor vasculature. In comparison with xenografted tumors derived from CD133--GSC, a highly vascularized anaplastic tumor, mimicking vasculogenic mimicry, was found in CD133+-GSC-derived tumor xenografts. Subsets of CD133+-GSC but not CD133--GSC were capable of vascular smooth muscle-like cell differentiation, in vitro and in vivo. In tumor xenografts, endothelium-associated CD31 gene was detected in implanted CD133--GSC and exclusively dispersed within the tumor tissues. Although, the detailed action mechanisms required further investigation, this study demonstrated the vasculogenic capacity of brain GSCs and their cellular plasticity. The results of expression of pro-vascular molecules and differentiation of vascular-like cells suggest that GSCs may contribute to form vessel-like structures and provide a blood supply for glioblastoma cells. In addition, although Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been used in clinical trials for cancer therapies, its pharmacological effects occur through a poorly understood mechanism. Here, we report that SAHA specifically triggers autophagy and reduces cell viability via promotion of apoptosis in the late phase of glioblastoma stem cells (GSCs). Using a cell line cultured from a glioblastoma biopsy, we investigated the properties and effects of GSCs under SAHA treatment in vitro. In vivo xenograft assays revealed that SAHA effectively caused tumor growth slowdown and the induction of autophagy. SAHA was sufficient to increase formation of intracellular acidic vesicle organelles, recruitment of LC3-II to the autophagosomes, potentiation of BECN1 protein levels, and reduced SQSTM1 levels. We determined that SAHA triggered autophagy through the downregulation of AKT-mTOR signaling, a major suppressive cascade of autophagy. Interestingly, upon depletion or pharmacological inhibition of autophagy, SAHA facilitates apoptosis and results in cell death at the early phase, suggesting that SAHA-induced autophagy functions probably act as a prosurvival mechanism. Furthermore, our results also indicated that the inhibition of SAHA-induced autophagy using chloroquine has synergistic effects that further increase apoptosis. Moreover, we found that a reduced dose of SAHA functioned as a potent modulator of differentiation and senescence. Taken together, our results provide a new perspective on the treatment of GSCs, indicating that SAHA is a promising agent for targeting GSCs through the induction of autophagy.
Chang, Ya-Ping, and 張雅評. "Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and inducing autophagy." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/93245095721695579026.
Повний текст джерела國立宜蘭大學
生物技術與動物科學系
103
The NLRP3 inflammasome is a caspase-1-containing multi-protein complex that controls the release of IL-1β and plays important roles in the development of inflammation-related disease. Here, we report that resveratrol, a polyphenolic compound naturally produced by plants, inhibits NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages. Resveratrol inhibits the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage. Resveratrol also induces autophagy by activating p38, and macrophages treated with an autophagy inhibitor are resistant to the suppressive effects of resveratrol. Our data indicate that resveratrol suppresses NLRP3 inflammasome activation by preserving mitochondrial integrity and by augmenting autophagy.
Lin, Pei-Jung, and 林珮蓉. "Arsenic treatment inhibits cell autophagy and leads to the occurrence of apoptosis." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/18121488819692751862.
Повний текст джерела國立清華大學
分子與細胞生物研究所
104
Arsenic is one of the environmental pollutants and a well-known carcinogen. Previous studies indicated that cytotoxicity caused by arsenic is recognized through generating oxidative stress, attenuating mitochondrial membrane potential, or influencing cell cycle to lead apoptosis. This study investigates the mechanism involved in the arsenic-induced cell death in Human Embryonic Kidney 293 (HEK 293) cells. Upon arsenic stimulation, PI3K/Akt signaling pathway is inhibited and leads to cytochrome c release from mitochondria which activates caspase 3 and apoptosis. However, PTEN is not participated in the PI3K/Akt signaling pathway. PTEN expression is reduced by arsenic treatment. Noticeably, the loss of PTEN is not due to the degradation of the protein, but presents in the insoluble fraction of the cells. The factor that assists protein refolding, heat shock protein 70 (Hsp 70), was also found in insoluble fraction. Concurrently, arsenic treatment inhibited the occurrence of autophagy in HEK 293 cells and caused an accumulation of LC3 in the cells. Administration of lysosomal activator (rapamycin) reduces the PTEN level in either soluble or insoluble fraction of the cells. The blockade of autophagy via reducing lysosomal activity caused the reduction of PI3K/Akt activity and led cells to apoptosis. Addition of rapamycin activates lysosomal activity and allows the cells to go through autophagy pathway. Our results reveal that arsenic treatment inhibits the lysosomal activity, and thus blocks the autophagy pathway. This blockade further reduces the activity of PI3K/Akt signaling pathway and leads to mitochondria-mediated apoptosis.
MacCallum, S., M. J. Groves, J. James, K. Murray, V. Appleyard, A. R. Prescott, Abed Alnaser A. A. Drbal, et al. "Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6." 2013. http://hdl.handle.net/10454/7250.
Повний текст джерелаTenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.
Liao, Ji-Der, and 廖記德. "Reversine inhibits cell growth and induces apoptosis and autophagy in lung cancer cells." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/34764319223200168724.
Повний текст джерела中華醫事科技大學
醫學檢驗生物技術系碩士班
101
Reversine ,2-(4-morpholinoanilino)-6-cyclohexylaminopurine, a small synthetic purine analogue, has been used for stimulating stem cell dedifferentiation. It has been reported that reversine is effective in tumor suppression, but it’s effect in lung cancer cells remains unclear. We treated lung cancer cell lines A549, H23 and H1299 with reversine and disseted the related pathways. First, we demonstrated reversine inhibited cell growth and colony formation. Further results revealed reversine induced cell cycle arrested at G2/M phase and formed polyploidy. The expressions of Aurora-A, Aurora-B, p-Akt(Ser473), p-GSK-3alpha(Ser21) and p-GSK-3beta(Ser9) were down-regulated The presence of cleaved caspase-3 and PARP demonstrated reversine in reversine treated cells could induce apoptosis. That the increased LC3-II protein was present after reversine treatment implied that the autophagy is also involved. Taken together, reversine suppressed cell growth of lung cancer cells and induced apoptosis as well as autophagy, which may be an unique advantage for developing novel therapeutic agents for treatment of lung cancers in the future.
Yi, Wan-Chien, and 萬建億. "Antipsychotic Clozapine Inhibits HCT116 Colorectal Cancer Cell Growth through ERK-Autophagy Signal Pathway." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/80651638753308842423.
Повний текст джерела國立臺灣海洋大學
生物科技研究所
99
Clozapine is an atypical antipsychotic used to treat refractory schizophrenia clinically. Some previous researches as well as clinical statistics indicated that schizophrenia patients taking antipsychotics have less incidence of developing cancer than normal people. Antipsychotics can inhibit cancer cell growth, but the mechanisms still need to further elucidate. Colorectal cancer is the third leading cause of mortality in western countries. The development of colorectal cancer is often associated with gene mutations such as APC, β-catenin and KRAS. In this study, human colorectal cancer cell line HCT116 is used to investigate antitumor ability and molecular mechanisms of clozapine. Preliminary data showed that clozapine inhibited proliferation of HCT116 in both time- and dosage-dependent manners by MTT and clonogenic assay. Clozapine also led to cell cycle arrest at G0/G1 phase and related cyclin-dependent kinase inhibitors p21 and p27 increased while protein expression of CDK6 and pRb (Ser795) decreased. Clozapine did not induce apoptosis by Annexin-V and western blot. However, clozapine induced autophgy (Type II cell death) by increasing LC3II, beclin-1 and Atg5. ERK inhibitor PD98059 inhibited the clozapine-induced increase of LC3II. It is suggested that the effect of clozapine on autophagy is mediated by ERK pathway. It should be further examined whether ERK-autophagy pathway involved in inhibition of clozapine on HCT116 cancer cell growth.
Chang, Yu-Teng, and 張譽騰. "Flavonoids Participate in the Regulatory Mechanisms of Antizyme Inhibitor in HL-60 Autophagy/ Differentiation/ Activation/ Apoptosis." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/76090874278192234590.
Повний текст джерела國立中興大學
生命科學系所
104
Antizyme inhibitor (AZI) has been thought to promote cancer cell proliferation, it’s caused between with antizyme (AZ) and ornithine decarboxylase (Ornithine decarboxylase, ODC; EC 4.1.1.17) regulatory mechanism. Flavonoids source from fruits, vegetables, tea, wine, seeds or roots of plants, widely considered to have antioxidant or anti-inflammatory response effect. In our study, we chose four kinds of flavonoids: Epigallocatechin gallate (EGCG)、 Baicalein、 Myricetin、 7,8-Dihydroxyflavone (7,8-DHF), explore its toxic effect in HL-60 immunity cancer cell, and hoped that in the future can be further developed into new drugs for the treatment of leukemia or other cancers. Above these four drugs have been found to inhibit the ornithine decarboxylase enzyme activity, in our laboratory previous study have found catechin composition were impacted AZI protein structure, so we transfected AZI gene into HL-60, then compare whether those flavonoids affect AZI structure and function further impact toxic effect in cells. Moreover, many researches revealed TPA besides caused HL-60 differentiate to macrophage and induced autophagy, activation, differentiation and apoptosis. Based on these study we treat both EGCG and TPA in HL-60 and compare with empty vector and overexpression of AZI. Our data demonstrate those four drugs both could cause HL-60 apoptosis, but EGCG and myricetin caused overexpression of AZI more cell death than empty vector. Co-treated with TPA and EGCG compare with TPA only increase autophagy, activation, differentiation and apoptosis, and overexpression of AZI more strengthened on autophagy, activation, differentiation and apoptosis in HL-60. These results proved that TPA can cause HL-60 differentiation, and after add EGCG accelerates differentiation to cell death ahead of time. Therefore, in the future treatment of human leukemia, by TPA can mix with EGCG as an adjunct to anti-cancer therapy as a guideline.
Wu, Mei-Yi, and 吳玫憶. "Chloroquine, An Autophagy Inhibitor, Enhances The Cytotoxicity of Gefitinib in Non Small Cell Lung Cancer Cells." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/69956317540921811835.
Повний текст джерела國立陽明大學
藥理學研究所
100
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for patients with non small cell lung cancers (NSCLCs). However, patients eventually develop drug resistance. Autophagy, one of the processes to degrading cellular proteins or organelles, reportedly facilitates anti-cancer treatments, including radiation and chemotherapies. In my thesis, two aims were focused, one was the involvement of autophagy in gefitinib-resistance and the other was the effect of chloroquine (CQ), an autophagy inhibitor by preventing formation of autophagolysosomes, on gefitinib-resistance. To serve this purpose, a novel acquired gefitinib-resistant cell line (PC-9/gef) was developed by continuous exposure of the parental PC-9/wt NSCLC cells (containing EGFR exon 19 deletion) to escalating concentrations of gefitinib. Three resistant clones of PC-9/gef cells were identified, including PC-9/gef B4, E3 and E7 cells. Using SRB assay, PC-9/gef cells were more resistant to gefitinib than PC-9/wt cells. The IC50 of gefitinib of PC-9/gef cells was 150-fold more than that of PC-9/wt cells. Compared with PC-9/wt cells, PC-9/gef B4 cells had higher basal LC3-II levels. 3-Methyladenine (3-MA, an early-phase autophagy inhibitor) ameliorated the LC3-II levels in both cells. Compared with PC-9/wt cells, PC-9/gef B4 cells appeared to be more sensitive to CQ-induced elevation in LC3-II levels. These data indicate that PC-9/gef B4 cells had a higher level of autophagy. At the same time, 3-MA inhibited cell survival of both cells in a concentration-dependent manner. However, CQ induced a more significant cytotoxicity in PC-9/gef B4 cells compared with PC-9/wt cells. These data suggest that autophagy may play a pro-survival role in cancer cell survival; the survival of PC-9/gef B4 cells appears to be more dependent on autophagy. In contrast to the 150-fold difference in IC50 of gefitinib, gefitinib concentration-dependently increased LC3-II levels in both cells; however, LC3-II 8 elevation by low dose of gefitinib were more evident in PC-9/gef B4 cells. The data from immunostaining supported this notion that more LC3-II puncta were observed in PC-9/gef B4 cells than in PC-9/wt cells. Furthermore, CQ enhanced gefitinib-induced LC3-II levels in both cells. Gefitinib potently reduced the cell survival of PC-9/wt cells; CQ was unable to potentiate gefitinib-induced cytotoxicity. As to PC-9/gef B4 cells, gefitinib alone induced moderate cell death of PC-9/gef B4 cells; CQ sensitized PC-9/gef B4 cells to the gefitinib-induced cytotoxicity. The cytotoxic mechanisms were investigated by measuring caspase-3 activation. Gefitinib induced significant activation of caspase-3 and CQ did not potentiate gefitinib-induced apoptosis in PC9/wt cells. In contrast, in PC-9/gef B4 cells, gefitinib induced slight increases in active caspase-3 levels ; CQ plus gefitinib showed significant elevation in caspase-3 levels, indicating that CQ may reverse resistance in PC-9/gef B4 cells. An in vivo model xenografting was performed using implanting PC-9/wt cells and PC-9/gef B4 cells. Oral administration of gefitinib significantly reduced the tumor growth of PC-9/wt cells. Combination of gefitinib plus CQ did not further suppress the tumor growth. In contrast, oral administration of gefitinib slightly reduced the tumor growth of PC-9/gef B4 cells. Combination of gefitinib plus CQ further suppressed the tumor growth. The pharmacodynamic study showed augmentation of caspase-9 activation in PC-9/gef B4 tumor tissues in mice treated with gefitinib and CQ. In conclusion, my study showed that PC-9/gef cells have higher basal level of autophagy, which may play a pro-survival role. Furthermore, CQ potentiated gefitinib-induced cytotoxicity in PC-9/gef B4 cells, indicating that CQ may partially reverse the gefitinib resistance. Accordingly, in addition to the consistent activation of ERK pathway in gefitinib resistance which can be overcome by ERK inhibitors, such as AZD6244, CQ and autophagy inhibitors may be a therapeutic strategy for gefitinib resistance.
Yu, Chen-Lin, and 尤振霖. "Pterostilbene Inhibits the Proliferation of HCC Cells in vitro by Inducing Autophagy and Apoptosis." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/n6d8jb.
Повний текст джерела中山醫學大學
醫學檢驗暨生物技術學系碩士班
102
Petrostilbene is a natural dimethyl analog of resveratrol and found in many grapes and berries, with multiple pharmacologic activities, including anti-inflammation, anti-oxidation and cancer prevention. Many studies showed that pterostilbene can induce apoptosis and autophagy in various cancer cell lines and further inhibit their viability. However, the exact mechanism of pterostilbene-aused growth inhibition in hepato- cellular carcinoma (HCC) cell lines remains unclear. The main goal of this study is to elucidate how pterostilbene inhibit cell proliferation of HCC cells. Results from MTT assay and DAPI staining showed that pterostilbene caused both dose- and time-dependent inhibition of viability of both cells while the morphology of both cells was changed into a more apoptotic fashion. Cell cycle analysis showed that the phase distribution was changed by pterostilbene treatment. However, the expression of caspase 3, 8 and 9 were not affected, indicating that caspase-independent apoptosis may be activated. Meanwhile, results form AO staining showed that pterostilbene treatment can increase the percentage of AVOs positive cells in both dose- and time-dependent manner. Furthermore, the expression level of LC3-II was also increased in both dose- and time-dependent manner by pterostilbene. In summary, pterostilbene inhibit the cellular viabilities of Huh 7 and SK-Hep 1 via cell cycle arrest and the activation of autophagy.
Cheng, Hui-Wen, and 鄭惠文. "Thioridazine, an antipsychotic agent, inhibits cancer stem cell growth and induces autophagy of Glioblastoma Multiforme." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/03732371190588805985.
Повний текст джерела國立陽明大學
生物藥學研究所
102
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. Glioblastoma stem cells (GSCs) have been proposed to be involved in tumorigenesis, tumor maintenance and therapeutic resistance. Currently, temozolomide is the only FDA-approved treatment for GBM. Therefore, there is an urgent need to discover novel candidate therapeutic drugs for GBM. Here, we identified thioridazine, an anti-psychotic drug, as a potential treatment for GBM via the Connectivity Map database. Thioridazine can cross the blood-brain barrier (BBB), providing a significant advantage over current drug delivery limitations. We demonstrate that thioridazine inhibits the cell viability of both GBM cells and GSCs. Thioridazine induces autophagy in GBM cells and GSCs, as evident by the up-regulation of LC3II, and up-regulates AMPK activity. Moreover, thioridazine induces ER stress in GBM cells. Finally, thioridazine suppresses GBM tumorigenesis and induces autophagy in vivo. The data suggest that thioridazine-induced autophagy has an anti-cancer effect in GBM through activation of AMPK. In summary, we repurpose the anti-psychotic drug, thioridazine, as a potent anti-GBM and anti-GBM cancer stem cell agent for potential clinical trial in the future.
Schafranek, Lisa Rhiannon. "Assessment of critical survival mechanisms exploited by BCR-ABL1+ cells to evade tyrosine kinase inhibitor-induced death: determination of novel therapeutic targets in chronic myeloid leukaemia." Thesis, 2014. http://hdl.handle.net/2440/92213.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2014
Chih-YunLiu and 劉知耘. "Targeting survivin by a novel small molecule inhibitor, YM155 induces autophagic cell death in human breast cancer cells." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/24942197536310680653.
Повний текст джерела國立成功大學
藥理學研究所
101
Despite hormone therapy, targeted therapy and chemotherapy have been developed to target different types of breast cancer; the current breast cancer treatments still have several limitations and undesired side-effects. Thus, it is important to develop novel strategies to treat breast cancer. Survivin (BIRC5) is a member of the inhibitor-of-apoptosis proteins family, and it has been shown to play important role in breast cancer development and progression. YM155 is a novel small molecule inhibitor of survivin. Despite YM155 is currently undergoing different phase II clinical trials including studies in patients with breast cancer, its effectiveness in targeting the estrogen receptor (ER) positive Tamoxifen-resistant breast cancer was seldom determined in the past. In addition, it is still unclear whether YM155 exhibits differential anti-breast cancer functions in different breast cancer subtypes. The purpose of this study is to determine the effectiveness of YM155 in targeting various types of breast cancer and its differential molecular mechanism of action in different breast cancer cell lines. Here, YM155 is equally effective in targeting both the parental ER-positive Tamoxifen-sensitive MCF7 and the MCF7-dervided ER-positive Tamoxifen-resistant breast cancer cells in vitro. YM155 is also effective in targeting the triple-negative MDA-MB-231 breast cancer cells. Surprisingly, Western blot analysis, immunofluorescent microscopy and autophagy/apoptosis inhibition assay revealed that targeting survivin by YM155 induced autophagic cell death, but not caspase-3 dependent apoptosis, in most of the tested breast cancer cell lines; despite it is widely believed that survivin inhibits apoptosis through physical interactions with caspase-3. Interestingly, YM155 also induced autophagy-dependent DNA damage in the treated breast cancer cells. Taken together, targeting survivin by YM155 induces autophagic cell death in breast cancer cells. Importantly, YM155 is a promising anti-cancer compound that has potential for the management of various types of breast cancer.