Relevant bibliographies by topics / Autophagy inhibitors

Academic literature on the topic 'Autophagy inhibitors'

Author: Grafiati
Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Autophagy inhibitors"

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Körholz, Katharina, Johannes Ridinger, Damir Krunic, Sara Najafi, Xenia F. Gerloff, Karen Frese, Benjamin Meder, et al. "Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma." Cells 10, no. 5 (April 24, 2021): 1001. http://dx.doi.org/10.3390/cells10051001.

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Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB—TFEB, forkhead boxO—FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.
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Rahman, Md Ataur, Yoonjeong Cho, Hongik Hwang, and Hyewhon Rhim. "Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons." Brain Sciences 10, no. 12 (December 9, 2020): 958. http://dx.doi.org/10.3390/brainsci10120958.

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O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and lipid molecules, are degraded and recycled. Here, we examined how three different OGT inhibitors, alloxan, BXZ2, and OSMI-1, modulate O-GlcNAcylation in rat cortical neurons, and their autophagic effects were determined by immunoblot and immunofluorescence assays. We found that the treatment of cortical neurons with an OGT inhibitor decreased O-GlcNAcylation levels and increased LC3-II expression. Interestingly, the pre-treatment with rapamycin, an mTOR inhibitor, further increased the expression levels of LC3-II induced by OGT inhibition, implicating the involvement of mTOR signaling in O-GlcNAcylation-dependent autophagy. In contrast, OGT inhibitor-mediated autophagy was significantly attenuated by 3-methyladenine (3-MA), a blocker of autophagosome formation. However, when pre-treated with chloroquine (CQ), a lysosomotropic agent and a late-stage autophagy inhibitor, OGT inhibitors significantly increased LC3-II levels along with LC3 puncta formation, indicating the stimulation of autophagic flux. Lastly, we found that OGT inhibitors significantly decreased the levels of the autophagy substrate p62/SQSTM1 while increasing the expression of lysosome-associated membrane protein 1 (LAMP1). Together, our study reveals that the modulation of O-GlcNAcylation by OGT inhibition regulates mTOR-dependent autophagy in rat cortical neurons.
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Yang, Cheng, Varsha Kaushal, Sudhir V. Shah, and Gur P. Kaushal. "Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells." American Journal of Physiology-Renal Physiology 294, no. 4 (April 2008): F777—F787. http://dx.doi.org/10.1152/ajprenal.00590.2007.

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Autophagy has emerged as another major “programmed” mechanism to control life and death much like “programmed cell death” is for apoptosis in eukaryotes. We examined the expression of autophagic proteins and formation of autophagosomes during progression of cisplatin injury to renal tubular epithelial cells (RTEC). Autophagy was detected as early as 2–4 h after cisplatin exposure as indicated by induction of LC3-I, conversion of LC3-I to LC3-II protein, and upregulation of Beclin 1 and Atg5, essential markers of autophagy. The appearance of cisplatin-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in RTEC provided further evidence for autophagy. The autophagy inhibitor 3-methyladenine blocked punctated staining of autophagosomes. The staining of normal cells with acridine orange displayed green fluorescence with cytoplasmic and nuclear components in normal cells but displayed considerable red fluorescence in cisplatin-treated cells, suggesting formation of numerous acidic autophagolysosomal vacuoles. Autophagy inhibitors LY294002 or 3-methyladenine or wortmannin inhibited the formation of autophagosomes but induced apoptosis after 2–4 h of cisplatin treatment as indicated by caspase-3/7 and -6 activation, nuclear fragmentation, and cell death. This switch from autophagy to apoptosis by autophagic inhibitors further suggests that the preapoptotic lag phase after treatment with cisplatin is mediated by autophagy. At later stages of cisplatin injury, apoptosis was also found to be associated with autophagy, as autophagic inhibitors and inactivation of autophagy proteins Beclin 1 and Atg5 enhanced activation of caspases and apoptosis. Our results demonstrate that induction of autophagy mounts an adaptive response, suppresses cisplatin-induced apoptosis, and prolongs survival of RTEC.
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Pasquier, Benoit. "Autophagy inhibitors." Cellular and Molecular Life Sciences 73, no. 5 (December 11, 2015): 985–1001. http://dx.doi.org/10.1007/s00018-015-2104-y.

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Chaikuad, Apirat, Sebastian E. Koschade, Alexandra Stolz, Katarina Zivkovic, Christian Pohl, Shabnam Shaid, Huiyu Ren, et al. "Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2)." Biochemical Journal 476, no. 5 (March 12, 2019): 875–87. http://dx.doi.org/10.1042/bcj20190038.

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Abstract Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 (Unc-51-like autophagy activating kinase 1) has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2 (Unc-51-like autophagy activating kinase 2). Here, we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor-binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provide structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.
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Janser, Félice, Olivia Adams, Vanessa Bütler, Anna Schläfli, Bastian Dislich, Christian Seiler, Dino Kröll, Rupert Langer, and Mario Tschan. "Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells." International Journal of Molecular Sciences 19, no. 10 (October 8, 2018): 3069. http://dx.doi.org/10.3390/ijms19103069.

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Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.
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Dykstra, Kaitlyn M., Hannah R. S. Fay, Ashish C. Massey, Neng Yang, Matthew Johnson, Scott Portwood, Monica L. Guzman, and Eunice S. Wang. "Inhibiting autophagy targets human leukemic stem cells and hypoxic AML blasts by disrupting mitochondrial homeostasis." Blood Advances 5, no. 8 (April 20, 2021): 2087–100. http://dx.doi.org/10.1182/bloodadvances.2020002666.

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Abstract Leukemia stem cells (LSCs) and therapy-resistant acute myeloid leukemia (AML) blasts contribute to the reinitiation of leukemia after remission, necessitating therapeutic interventions that target these populations. Autophagy is a prosurvival process that allows for cells to adapt to a variety of stressors. Blocking autophagy pharmacologically by using mechanistically distinct inhibitors induced apoptosis and prevented colony formation in primary human AML cells. The most effective inhibitor, bafilomycin A1 (Baf A1), also prevented the in vivo maintenance of AML LSCs in NSG mice. To understand why Baf A1 exerted the most dramatic effects on LSC survival, we evaluated mitochondrial function. Baf A1 reduced mitochondrial respiration and stabilized PTEN-induced kinase-1 (PINK-1), which initiates autophagy of mitochondria (mitophagy). Interestingly, with the autophagy inhibitor chloroquine, levels of enhanced cell death and reduced mitochondrial respiration phenocopied the effects of Baf A1 only when cultured in hypoxic conditions that mimic the marrow microenvironment (1% O2). This indicates that increased efficacy of autophagy inhibitors in inducing AML cell death can be achieved by concurrently inducing mitochondrial damage and mitophagy (pharmacologically or by hypoxic induction) and blocking mitochondrial degradation. In addition, prolonged exposure of AML cells to hypoxia induced autophagic flux and reduced chemosensitivity to cytarabine (Ara-C), which was reversed by autophagy inhibition. The combination of Ara-C with Baf A1 also decreased tumor burden in vivo. These findings demonstrate that autophagy is critical for mitochondrial homeostasis and survival of AML cells in hypoxia and support the development of autophagy inhibitors as novel therapeutic agents for AML.
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Holen, I., P. B. Gordon, and P. O. Seglen. "Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity." Biochemical Journal 284, no. 3 (June 15, 1992): 633–36. http://dx.doi.org/10.1042/bj2840633.

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The protein phosphatase inhibitor okadaic acid suppressed autophagy completely in isolated rat hepatocytes, as measured by the sequestration of electroinjected [3H]raffinose into sedimentable autophagic vacuoles. Okadaic acid was effectively antagonized by the general protein kinase inhibitors K-252a and KT-5926, the calmodulin antagonist W-7, and by KN-62, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMK-II). These inhibitors also antagonized a cytoskeleton-disruptive effect of okadaic acid, manifested as the disintegration of cell corpses after breakage of the plasma membrane. CaMK-II, or a closely related enzyme, would thus seem to play a role in the control of autophagy as well as in the control of cytoskeletal organization.
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Fu, Yuanyuan, Qianqian Gu, Li Luo, Jiecheng Xu, Yuping Luo, Fan Xia, Fanghai Han, et al. "New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function." Cancers 12, no. 6 (June 10, 2020): 1523. http://dx.doi.org/10.3390/cancers12061523.

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Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.
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Bohusné Barta, Bettina, Ágnes Simon, Lőrinc Nagy, Titanilla Dankó, Regina Eszter Raffay, Gábor Petővári, Viktória Zsiros, Anna Sebestyén, Ferenc Sipos, and Györgyi Műzes. "Survival of HT29 cancer cells is influenced by hepatocyte growth factor receptor inhibition through modulation of self-DNA-triggered TLR9-dependent autophagy response." PLOS ONE 17, no. 5 (May 12, 2022): e0268217. http://dx.doi.org/10.1371/journal.pone.0268217.

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HGFR activation drives the malignant progression of colorectal cancer, and its inhibition displays anti-autophagic activity. The interrelated role of HGFR inhibition and TLR9/autophagy signaling in HT29 cancer cells subjected to modified self-DNA treatments has not been clarified. We analyzed this complex interplay with cell metabolism and proliferation measurements, TLR9, HGFR and autophagy inhibitory assays and WES Simple Western blot-based autophagy flux measurements, gene expression analyses, immunocytochemistry, and transmission electron microscopy. The overexpression of MyD88 and caspase-3 was associated with enhanced HT29 cell proliferation, suggesting that incubation with self-DNAs could suppress the apoptosis-induced compensatory cell proliferation. HGFR inhibition blocked the proliferation-reducing effect of genomic and hypermethylated, but not that of fragmented DNA. Lowest cell proliferation was achieved with the concomitant use of genomic DNA, HGFR inhibitor, and chloroquine, when the proliferation stimulating effect of STAT3 overexpression could be outweighed by the inhibitory effect of LC3B, indicating the putative involvement of HGFR-mTOR-ULK1 molecular cascade in HGFR inhibitor-mediated autophagy. The most intense cell proliferation was caused by the co-administration of hypermethylated DNA, TLR9 and HGFR inhibitors, when decreased expression of both canonical and non-canonical HGFR signaling pathways and autophagy-related genes was present. The observed ultrastructural changes also support the context-dependent role of HGFR inhibition and autophagy on cell survival and proliferation. Further investigation of the influence of the studied signaling pathways and cellular processes can provide a basis for novel, individualized anti-cancer therapies.
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Dissertations / Theses on the topic "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.

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HIV protease inhibitors (PI) are core components of Highly Active Antiretroviral Therapy (HAART). HIV PIs are extremely effective at suppressing viral load, but have been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease. Recent studies indicate that activation of endoplasmic reticulum (ER) stress is an important cellular mechanism underlying HIV PI-induced dysregulation of lipid metabolism. However, the exact role of ER stress in HIV PI-associated lipodystrophy and dyslipidemia remains to be identified. Hepatocytes and adipocytes are important players in regulating lipid metabolism and the inflammatory state. Dysfunction of these two cell types is closely linked to various metabolic diseases. In this dissertation research, we aimed to define the role of activation of ER stress in HIV PI-induced dysregulation of lipid metabolism in adipocytes and hepatocytes and further identifty the potential molecular mechanisms. Both cultured and primary mouse adipocytes and hepatocytes were used to examine the effect of individual HIV PIs on ER stress activation and lipid metabolism. The results indicated that HIV PIs differentially activate ER stress through depletion of ER calcium stores, activating the unfolded protein response (UPR). UPR activation further lead to an alteration of cellular differentiation through downstream transcription factor CHOP. At the same time, HIV PIs also altered adipogenesis via differential regulation of the adipogenic transcription factor PPARγ. HIV PI-induced ER stress was closely linked to dysregulation of autophagy activation through CHOP, and upstream ATF-4, signaling pathways. In hepatocytes, the integrase inhibitor raltegravir abrogated HIV PI-induced lipid accumulation by inhibiting ER stress activation and dysregulation of autophagy pathway. Our studies suggest that both ER stress and autophagy are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes and hepatocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV HAART-treated patients.
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Khan, 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.

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As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.
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Martin, Mackenzie. "Targeting Tau Degradation by Small Molecule Inhibitors for Treatment of Tauopathies." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6314.

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Tauopathies are neurodegenerative diseases that affect millions of people around the world. Tauopathies include more than 20 neurodegenerative diseases. Some of the most common tauopathies are Alzheimer’s disease (AD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), Pick’s disease, corticobasal degeneration, progressive supranuclear palsy (PSP), agyrophillic grain disease, and amyotrophic lateral sclerosis (ALS). These diseases can cause significant memory loss, behavioral changes, motor deficits and speech impairments. Tauopathies stem from accumulation of the microtubule associated protein tau (MAPT). Tau stabilizes microtubules and helps with axonal transport. In a disease state tau becomes hyperphosphorylated and truncated leading to its aggregation. More recently tau has been shown to propagate from cell to cell potentially acting as a signaling molecule that contributes to disease progression. In addition during disease, tau mislocalizes to dendrites leading to synaptic dysfunction. This mislocalization may also lead to subsequent neurodegeneration. Today, many strategies have been implemented to treat tauopathies. Some of these strategies include kinase inhibitors, immunotherapy, tau aggregation inhibitors, and microtubule-stabilizing compounds. However none these strategies have been effective in stopping tau pathology nor do they address tau degradation pathways. Therefore we hypothesized that utilizing small molecules that target degradation pathways such as autophagy or proteasomal degradation would improve clearance of aberrant tau. We previously showed that a natural product (+)-aR,11S-myricanol (1) from Myrica cerifica (bayberry/southern wax myrtle) root bark reduced levels of tau. In this study we discovered that 1 is composed of two enantiomers and two possible atropisomers. We found that one enantiomer (-)-aS,11R-myricanol (3) was responsible for the anti-tau activity of 1 in multiple models of tauopathy. We also found that 3 selectively targets and lowers specific tau species. To better understand how these tau species were being reduced we took a non-biased approach and subjected 3 treated samples to stable isotope labeling by amino acids in cell culture (SILAC) mass spectrometry (MS) proteomic analysis. We found that autophagy pathways were most affected by 3 and that 3 was predicted to mimic the drug rapamycin, a well-established macroautophagy activator. In addition we confirmed our MS findings by simultaneously giving 3 treated cells an autophagy inhibitor which blocked 3’s tau reductions. Moreover we created a tetralin derivative of 1, 13, that produced the same effects on tau as 3 but did not rely upon stereochemistry for its activity. This work supports targeting the autophagy degradation pathway as a viable approach to improving aberrant tau accumulation. In order to further support our hypothesis, we collected and screened several known heat shock protein 70 (Hsp70) inhibitors and tau aggregation inhibitors for cellular anti-tau activity. While it is known that Hsp70 inhibition facilitates tau clearance through proteasomal degradation, it is not known what role tau aggregation inhibition plays in the cellular degradation of tau. Moreover understanding which inhibitory activity contributes most to tau degradation would lead to the creation of better drug scaffolds. In this study, we found that several Hsp70 inhibitors from different scaffold backbones had varying effects on tau degradation. The rhodacyanine and phenothiazine compounds were most effective at lowering cellular tau while the adenosine analog, sulfonamide, dihyropyrimidine, piperidine-3-carboxamide, phenoxy-N-arylacetamide, and flavonol, were not as effective. We also examined the effects of several tau aggregation inhibitor scaffolds such as the carbocyanine, oleuropein, anthraquinone, aminothienopyridazine, hydroxytyrosol and rhodanine on tau expression reduction. We found that none had effective tau reductions except the carbocyanine. However when we performed a lactate dehydrogenase (LDH) assay, carbocyanine was shown to be extremely toxic. These results lead us to further investigate if the tau expression reducing Hsp70 inhibitors had anti-tau aggregation activity and if the tau aggregation inhibitors had any Hsp70 inhibitory activity. We discovered that many of the Hsp70 inhibitors also had anti-tau aggregation activity while none of the aggregation inhibitors had Hsp70 inhibitory activity. We found a positive correlation between tau expression reductions and anti-tau aggregation activity for the Hsp70 inhibitors. Our work demonstrates that both Hsp70 activity and tau aggregation in vitro best predicts anti-tau activity of small molecules. Also these dual acting Hsp70 inhibitors support our hypothesis that targeting the degradation pathways can improve tau clearance. Overall, this work indicates the importance of targeting degradation pathways to improve tau clearance. Utilizing small molecules that have dual activities against tau could prove beneficial as a novel therapeutic approach to treat tauopathies. In addition using small molecules that target different degradation pathways simultaneously could be another viable therapeutic strategy for treatment of tauopathies.
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Timme, Cindy R. "Drug Resistance Mechanisms to Gamma-secretase Inhibitors in Human Colon Cancer Cells." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4954.

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Colorectal cancer is the third leading cause of cancer-related mortality. Much progress has been achieved in combating this disease with surgical resection and chemotherapy in combination with targeted drugs. However, most metastatic patients develop drug resistance so new modalities of treatment are needed. Notch signaling plays a vital role in intestinal homeostasis, self-renewal, and cell fate decisions during post-development and is activated in colorectal adenocarcinomas. Under debate is its role in carcinomas and metastatic disease. In theory, blocking Notch activation using gamma-secretase inhibitors (GSIs) may show efficacy alone or in combination with chemotherapy in the treatment of colon cancer. In Chapter Three, we tested the capacity for GSIs to synergize with oxaliplatin in colon cancer cell lines and evaluated the underlying molecular mechanisms. GSI alone had no effect on colon cancer cell lines. Surprisingly, we show that GSIs blocked oxaliplatin-induced apoptosis through increased protein levels of the anti-apoptotic Bcl-2 proteins Mcl-1 and/or Bcl-xL. Restoration of apoptosis was achieved by blocking Mcl-1 and/or Bcl-xL with obatoclax (an anti-apoptotic Bcl-2 agonist) or siRNA. An unexpected result was the induction of cell death with the combination of GSI and obatoclax. In Chapter Four, we examined the mechanism of GSI + obatoclax-mediated cell death. We found that apoptosis played a minimal role. Rather, we identified blockage of cytoprotective autophagy played a causative role. Interestingly, we also saw autophagy induction in GSI-treated cells, which could explain the insensitivity of colon cancer cells to GSI. When autophagy was blocked in GSI-treated cells, cells became sensitive to GSI and cell death was elicited. The mechanism by which induction of autophagy occurs in GSI- treated cells is an area for further research. Overall, our work questions the validity of the use of GSIs in the treatment of colorectal cancers. We show that GSIs may block apoptosis and induce cytoprotective autophagy simultaneously, resulting in increased drug resistance and cellular survival. Whether these two cellular survival processes occurs in patients needs to be examined before GSIs can be utilized in a clinical setting. If so, these two hurdles must be overcome.
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Robke, 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.

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Rummelt, 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.

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Peng, 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.

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Peng, 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.

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Garivet, 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.

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Meza, Daniel. "Sphingosine Kinase 1 Inhibitor, A Novel Inducer of Autophagy." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1871.

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Autophagy is the process of “cell self-eating” which has been implicated both in cell survival and cell death. Sphingosine kinase 1 (SphK1) regulates the intracellular balance between ceramide and sphingosine, bioactive lipids associated with cell death, and sphingosine-1-phosphate (S1P), whose actions are associated with survival and proliferation. Previous studies have implicated upregulation of SphK1 in the induction of autophagy. In this study, SK1-I, a SphK1 specific competitive inhibitor, induced autophagy in a concentration and time dependent manner in HCT116 colorectal carcinoma cells. This autophagic response was observed to be more intense in wild type p53 expressing HCT116 cells than in p53 null cells and ultimately led to non-apoptotic death in wild type and apoptotic death in p53 null cells. In agreement, cell death in wild type cells was not accompanied by cleavage of polyADP ribose polymerase, a hallmark of apoptosis. Knockdown of Beclin 1 demonstrated that it and its binding partners do not have a significant role in the induction of autophagy in response to SK1-I treatment. Similarly, mTORC1 signaling was not observed. In contrast, SK1-I markedly decreased Akt phosphorylation. However, this might not be the sole factor important for SK1-I induced autophagy, as pharmacological inhibition of Akt only led to a comparatively weak autophagic response. Indeed, phosphorylation of the endoplasmic reticulum (ER) stress marker eIF2 α, was greatly reduced, suggesting that an ER mediated mechanism also contributes to SK1-I induced autophagy. Thus, SK1-I induced autophagy was likely triggered by ER stress signaling and led to non-apoptotic cell death in the more highly autophagic wild type 53 expressing cells. These results suggest that an isotype specific SphK1 inhibitor might be a useful adjunct for the treatment of cancer or other diseases in which enhancement of cytotoxicity or autophagy is desirable.
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Book chapters on the topic "Autophagy inhibitors"

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Kominami, E., T. Obshita, and N. Katunuma. "Functional shares of cathepsins B, H and L in autophagy and heterophagy." In Cysteine Proteinases and their Inhibitors, edited by Vito Turk, 229–38. Berlin, Boston: De Gruyter, 1986. http://dx.doi.org/10.1515/9783110846836-026.

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Nyfeler, Beat, Philip Bergman, Christopher J. Wilson, and Leon O. Murphy. "Quantitative Visualization of Autophagy Induction by mTOR Inhibitors." In Methods in Molecular Biology, 239–50. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-430-8_14.

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Konstantinidis, Georgios, Sonja Sievers, and Yao-Wen Wu. "Identification of Novel Autophagy Inhibitors via Cell-Based High-Content Screening." In Autophagy in Differentiation and Tissue Maintenance, 187–95. New York, NY: Springer New York, 2018. http://dx.doi.org/10.1007/7651_2018_125.

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Wen, Runxia H., Aaron D. Loewen, Ruanne Y. J. Vent-Schmidt, and Orson L. Moritz. "Autophagy Induction by HDAC Inhibitors Is Unlikely to be the Mechanism of Efficacy in Prevention of Retinal Degeneration Caused by P23H Rhodopsin." In Retinal Degenerative Diseases, 401–5. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-27378-1_66.

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Deen, Nadia S., Jacinta P. Lee, and James Harris. "Inducing and Inhibiting Autophagy to Investigate Its Interactions with MIF." In Macrophage Migration Inhibitory Factor, 147–58. New York, NY: Springer US, 2019. http://dx.doi.org/10.1007/978-1-4939-9936-1_13.

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Göder, Anja, Nisintha Mahendrarajah, and Oliver H. Krämer. "Detection of Autophagy Induction After HDAC Inhibitor Treatment in Leukemic Cells." In Methods in Molecular Biology, 3–10. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-6527-4_1.

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Singh, Tejveer, Arun Sidram Kharat, Brijesh Rathi, and Dhruv Kumar. "Designing metabolic target-specific inhibitors for cancer therapy." In Autophagy and Metabolism, 239–80. Elsevier, 2022. http://dx.doi.org/10.1016/b978-0-323-99879-6.00011-0.

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Moriyasu, Yuji, and Yuko Inoue. "Chapter Thirty‐Two Use of Protease Inhibitors for Detecting Autophagy in Plants." In Methods in Enzymology, 557–80. Elsevier, 2008. http://dx.doi.org/10.1016/s0076-6879(08)03232-1.

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Fukase, Naomasa, Ingrid K. Stake, Yoichi Murata, William S. Hambright, Sudheer Ravuri, Marc J. Philippon, and Johnny Huard. "Interventional Strategies to Delay Aging-Related Dysfunctions of the Musculoskeletal System." In Muscle Cell and Tissue - Novel Molecular Targets and Current Advances [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.97311.

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Aging affects bones, cartilage, muscles, and other connective tissue in the musculoskeletal system, leading to numerous age-related pathologies including osteoporosis, osteoarthritis, and sarcopenia. Understanding healthy aging may therefore open new therapeutic targets, thereby leading to the development of novel approaches to prevent several age-related orthopaedic diseases. It is well recognized that aging-related stem cell depletion and dysfunction leads to reduced regenerative capacity in various musculoskeletal tissues. However, more recent evidence suggests that dysregulated autophagy and cellular senescence might be fundamental mechanisms associated with aging-related musculoskeletal decline. The mammalian/mechanical target of Rapamycin (mTOR) is known to be an essential negative regulator of autophagy, and its inhibition has been demonstrated to promote longevity in numerous species. Besides, several reports demonstrate that selective elimination of senescent cells and their cognate Senescence-Associated Secretory Phenotype (SASP) can mitigate musculoskeletal tissue decline. Therefore, senolytic drugs/agents that can specifically target senescent cells, may offer a novel therapeutic strategy to treat a litany of age-related orthopaedic conditions. This chapter focuses on osteoarthritis and osteoporosis, very common debilitating orthopaedic conditions, and reviews current concepts highlighting new therapeutic strategies, including the mTOR inhibitors, senolytic agents, and mesenchymal stem cell (MSC)-based therapies.
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Ugale, Rajesh R., and Lopmudra Sarode. "Emerging Therapeutic Approaches for Neurodegenerative Diseases." In Neurodegenerative Diseases - Multifactorial Degenerative Processes, Biomarkers and Therapeutic Approaches (First Edition), 161–98. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/9789815040913122010013.

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The most common neurodegenerative diseases (ND) include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), as well as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Protein misfolding and aggregation are the key hallmarks of these neurodegenerative diseases, which may lead to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. Usually, ND is diagnosed at a very advanced stage and conventional therapies are directed at treating neurological symptoms but have no effect on disease progression. In general, several pathological processes contributes to misfolding proteins/protein aggregates and their postconsequences, including impairment of autophagy, microtubule destabilization, neuroinflammation, proteostasis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, calcium homeostasis, and neurogenesis impairment. Indeed, several signaling pathways critically linked with these pathological processes are now becoming attractive targets and investigated for their beneficial effects by restricting the progression of ND. In particular, certain signaling mechanisms and proteins found to show an integral involvement in the pathogenesis of ND and had shown promising results in preclinical and/or clinical contexts. For ex; novel autophagy stimulators, drugs acting on mTOR, NRF2, TLR, purinergic signaling; drugs acting on neuroinflammatory signaling pathways, Heat Shock Proteins (HSP), sestrins, sirtuins, some PDE-inhibitors, miRNA’s have gained a lot of attention in the therapy of ND and are included in the following discussion.
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Conference papers on the topic "Autophagy inhibitors"

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Amaravadi, Ravi. "Abstract IA25: Autophagy: A potentially druggable resistance mechanism to PI3K/mTOR inhibitors." In Abstracts: AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; September 14-17, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-8514.pi3k14-ia25.

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Yuan, Junying, Helin Vakifahmetoglu-Norberg, Hongguang Xia, Junli Liu, Ying Li, Minsu Kim, and Dawei Ma. "Abstract SY36-03: Development of small-molecule inhibitors of autophagy as anticancer therapy." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-sy36-03.

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Wu, Zhaoju, Pei-Ching Chang, Joy C. Yang, Cheng-Ying Chu, Ling-Yu Wang, Nien-Tsu Chen, Ai-Hong Ma, et al. "Abstract 4684: Autophagy blockade sensitizes prostate cancer cells towards Src family kinase inhibitors." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-4684.

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Piao, Shengfu, Arabinda Samanta, Xiao-hong Ma, Quentin Mcafee, Ben Wilkins, James Christensen, Peter O'Dwyer, and Ravi K. Amaravadi. "Abstract 1679A: HLTF gene silencing predicts sensitivity to lysosomal autophagy inhibitors in cancer cells." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-1679a.

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Vomero, M., A. Capozzi, C. Barbati, T. Colasanti, V. Manganelli, F. Ceccarelli, FR Spinelli, et al. "FRI0028 In vitro inhibitory effect of etanercept on autophagy: a new mechanism of action of tnf inhibitors in rheumatoid arthritis." In Annual European Congress of Rheumatology, 14–17 June, 2017. BMJ Publishing Group Ltd and European League Against Rheumatism, 2017. http://dx.doi.org/10.1136/annrheumdis-2017-eular.5061.

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Yih, Ling-Huei, Rajesh Kakadiya, Yi-Chen Wu, Hsiao-Hui Kuo, and Tsann-Long Su. "Abstract 2754: Cinnamoyl quinolines are novel autophagy inhibitors and enhance antitumor activity of 2-deoxyglucose." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2754.

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Keyomarsi, K., S. Vijayaraghavan, C. Karakas, I. Doostan, X. Chen, T. Bui, KK Hunt, and D. Tripahty. "Abstract P5-04-03: Palbociclib synergizes with autophagy inhibitors to induce senescence in breast cancer." In Abstracts: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.sabcs16-p5-04-03.

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Humbert, Magali, Michaela Medová, Daniel M. Aebersold, Mario P. Tschan, and Yitzhak Zimmer. "Abstract 1909: Cytoprotective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1909.

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Vazquez-Ortiz, Guelaguetza, Cristine L. Chisholm, Ruili Huang, Cuiling Li, Xiaoling Xu, Wang Rui-Hong, and Chuxia Deng. "Abstract 2744: Identification of synergistic effect of autophagy inhibitors and resveratrol on BRCA1 mutant cancer cells." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2744.

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Yali, Qi, Wang Hongyan, Zhao Dali, Liu Xiaodong, and Gong Shouliang. "Effects of inducers or inhibitors of autophagy and apoptosis combined with ionizing radiation on MCF-7 cells." In 2011 International Conference on Human Health and Biomedical Engineering (HHBE). IEEE, 2011. http://dx.doi.org/10.1109/hhbe.2011.6028045.

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Reports on the topic "Autophagy inhibitors"

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Shaw, Reuben J. Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors. Fort Belvoir, VA: Defense Technical Information Center, April 2014. http://dx.doi.org/10.21236/ada604191.

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