scholarly journals The Effect of the Combinations of 5-Fluorouracil, Leptin and Leptin Antagonist in Glioblastoma

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 19
Author(s):  
Taşpinar ◽  
Denizler ◽  
Taşpinar
Keyword(s):  
Brain Tumor ◽  
Cell Lines ◽  
Poor Prognosis ◽  
Leptin Receptor ◽  
Cell Type ◽  
Therapeutic Approaches ◽  
Cytotoxic Effects ◽  
New Therapeutic Approaches ◽  
Aggressive Form ◽  
The Relationship

Glioblastoma (GB) is the most aggressive form of brain tumor and resistant to chemotherapy. New therapeutic approaches are needed to improve the efficacy of chemotherapy. It was reported that there may be a relationship between obesity and poor prognosis in GB treatment. However, there is no study investigating the relationship between leptin, leptin receptor and chemotherapy in GB. The aim of this study was to investigate the cytotoxic effects of 5-Fluorouracil (5-FU) in the treatment of GB in the presence of leptin and leptin receptor antagonist SHLA. LN-405, T98G and U373-MG GB cell lines were used for this purpose. The cytotoxic effects of these molecules in both single and combination were determined by MTT. The sensitivities of GB cell lines to 5-FU were found to be different and leptin and SHLA had no cytotoxic effects in GB cells. It was determined that leptin increased 5-FU toxicity by 8–57% depending on 5-FU dose and cell type in all three cell lines in combination groups. A similar effect was detected in combinations of SHLA with 5-FU (6–58%). This is the first study to show that combinations of 5-FU with leptin and SHLA increase the cytotoxicity of 5-fluorouracil in cancer.

Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives

2018 ◽  
Vol 18 (2) ◽  
pp. 166-181 ◽  
Author(s):  
Antonio Marra ◽  
Cristina R. Ferrone ◽  
Celeste Fusciello ◽  
Giosue Scognamiglio ◽  
Soldano Ferrone ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Driver Mutations ◽  
Targeted Agents ◽  
Therapeutic Approaches ◽  
Aggressive Form ◽  
Immune Escape Mechanisms

Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation.

scholarly journals Shaping proteostasis at the cellular, tissue, and organismal level

2017 ◽  
Vol 216 (5) ◽  
pp. 1231-1241 ◽  
Author(s):  
Ambre J. Sala ◽  
Laura C. Bott ◽  
Richard I. Morimoto
Keyword(s):  
Cellular Tissue ◽  
Degenerative Diseases ◽  
Cell Type ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Precise Understanding ◽  
Systemic Level ◽  
Cell Type Specific ◽  
Multicellular Organisms ◽  
Pn Regulation

The proteostasis network (PN) regulates protein synthesis, folding, transport, and degradation to maintain proteome integrity and limit the accumulation of protein aggregates, a hallmark of aging and degenerative diseases. In multicellular organisms, the PN is regulated at the cellular, tissue, and systemic level to ensure organismal health and longevity. Here we review these three layers of PN regulation and examine how they collectively maintain cellular homeostasis, achieve cell type-specific proteomes, and coordinate proteostasis across tissues. A precise understanding of these layers of control has important implications for organismal health and could offer new therapeutic approaches for neurodegenerative diseases and other chronic disorders related to PN dysfunction.

scholarly journals Neuroblastoma-targeted Anticancer Drug Delivery

2021 ◽  
Author(s):  
Safiye Aktaş ◽  
Özde Elif Gökbayrak ◽  
Aylin Erol ◽  
Hatice Nur Olgun
Keyword(s):  
Drug Delivery ◽  
Bone Marrow ◽  
Poor Prognosis ◽  
Protein Stabilization ◽  
Newly Diagnosed ◽  
Therapeutic Approaches ◽  
Regional Lymph Nodes ◽  
Anticancer Drug Delivery ◽  
New Therapeutic Approaches ◽  
Late Stages

Neuroblastoma (NB) is the most common solid tumor in pediatric cases. NB accounts for about 8% of malignancies in patients younger than 15 years, and since 50% of newly diagnosed cases metastasize to regional lymph nodes, bone marrow, bone, liver, and skin, the disease is usually diagnosed in its late stages. Overexpression of N-MYC, which is characterized by poor prognosis in NB, changes the progression of the disease and the course of the treatment. Targeting these pathways may be a treatment option in NB, since the mTOR and AURKA pathways interact with N-MYC and directly cause protein stabilization. The widespread use of conventional chemotherapeutics has some limitations associated with their common side effects and the bioavailability of the drugs. New therapeutic approaches have focused on nanoparticle (NP) -based therapies, and chemoimmunoagents in the form of many NPs are being tried in NB. Here, we review new therapeutic approaches that would help to treat NB.

scholarly journals RDNA-14. RADIATION-INDUCED miR-4516 CONTRIBUTES TO RADIO-RESISTANCE AND PROMOTES AGGRESSIVE PHENOTYPE IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi209-vi210
Author(s):  
Ebin Sebastian ◽  
Tiantian Cui ◽  
Erica Hlavin Bell ◽  
Joseph McElroy ◽  
Benjamin Johnson ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Cell Viability ◽  
Cell Lines ◽  
Poor Prognosis ◽  
Radiation Treatment ◽  
Critical Role ◽  
Luciferase Reporter ◽  
Glioblastoma Cell ◽  
Clonogenic Assays ◽  
Glioblastoma Cell Lines

Abstract BACKGROUND Glioblastoma is the most aggressive brain tumor with poor prognosis despite the best available treatment. MicroRNAs (miRNAs) are emerging as promising, novel prognostic biomarkers and therapeutic targets in glioblastoma. In a previous study, we demonstrated that miR-4516 predicts poor prognosis and functions as an oncogene in glioblastoma. Aim of the current study is to examine the role miR-4516 in radiation resistance and identify downstream targets contributing to this phenotype METHODS Radiosensitization was evaluated by cell viability and clonogenic assays. Cell apoptosis was evaluated using flow cytometry and immunoblotting. Potential targets of miR-4516 were identified using bioinformatic analysis (Targetscan and miRDB) and confirmed by luciferase reporter assays. Results were validated using immunoblotting. miR-4516 expression in glioblastoma cell lines after radiation treatment was quantified by qRT-PCR. RESULTS Expression of miR-4516 was increased up to 15 fold following radiation treatment, peaking at around 15min-60 min in primary and established glioblastoma cell lines including GBM 08-387, GBM 30 and U87-MG. Furthermore, inhibition of miR-4516 sensitized GBM 08-387, GBM30 and U87-MG cells to radiation in comparison to control groups as determined by cell viability and clonogenic assays. Further, miR-4516 inhibition induced apoptosis in these cell lines following radiation treatment. While conducting mechanistic studies, we found that the tumor-promoting function of miR-4516 was, in part, mediated by inhibition of p21 and PTPN14, two direct targets of miR-4516 CONCLUSION Our data suggest that radiation induces the expression of miR-4516 in glioblastoma cell lines. This miRNA plays a critical role in radio-resistance and promotes aggressive phenotypes in glioblastoma and therefore, functional analyses of its target pathways may uncover novel therapeutically vulnerable target(s) in glioblastoma. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and OSU-CCC (all to AC). The Ton and Patricia Bohnenn Fund for Neuro_Oncology Research (to PR).

scholarly journals What Is Recent in Pancreatic Cancer Immunotherapy?

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Elena Niccolai ◽  
Domenico Prisco ◽  
Mario Milco D'Elios ◽  
Amedeo Amedei
Keyword(s):  
Pancreatic Cancer ◽  
Poor Prognosis ◽  
Advanced Disease ◽  
Active Immunotherapy ◽  
Therapeutic Approaches ◽  
Standard Chemotherapy ◽  
New Therapeutic Approaches ◽  
The Poor ◽  
Digestive Cancers

Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor responsein vivo.

scholarly journals MiR-148a-3p suppresses the progression of gastric cancer cells through targeting ATP6AP2

2020 ◽  
Vol 19 (9) ◽  
pp. 1821-1826
Author(s):  
Xiaosheng Jin ◽  
Peipei Cai ◽  
Zhengchao Shi ◽  
Fangpeng Ye ◽  
Tingting Ji ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Viability ◽  
Cell Line ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Epithelial Cell Line ◽  
Therapeutic Approaches ◽  
Gastric Cancer Cells ◽  
Expression Levels ◽  
New Therapeutic Approaches

Purpose: Gastric cancer (GC) is one of the most frequent tumors with high mortality rate, worldwide. A proper understanding of the mechanism  underlying its progression is required for its diagnosis and development of novel treatment option. MicroRNAs are associated with the development and advancement of different types of cancer, including GC. The current research was aimed at investigating the molecular and biological function of miR-148a-3p in GC development.Methods: A human normal gastric epithelial cell line, GES-1 (control) as well as four GC cell lines (NUGC-4, SNU-520, STKM-2 and MKN-74) were employed for the study. MiR-148a-3p and ATP6AP2 expression levels in GC cell lines were examined by RT-qPCR technique. Transfection procedure was used to upregulate miR-148a-3p expression in the MKN-45 cell line. MTT assay was utilized to evaluate cell viability in GC cell lines. The molecular interaction between miR-148a-3p and ATP6AP2 was predicted using bioinformatics system and the prediction was then validated by luciferase reporter assay.Results: Expression levels of miR-148-3p was low, whilst that of ATP6AP2 was high in GC cell lines. MiR-148a-3p overexpression resulted in the reduction of cell viability in GC cell lines. More so, it was confirmed that miR-148-3p, as a post-transcriptional regulator inhibited ATP6AP2 expression by having a negative association with it in GC cells. More so, ATP6AP2 was found to be a direct target of miR-148a-3p.Conclusion: Our results revealed that miR-148a-3p plays a crucial function in GC development through targeting ATP6AP2. This finding could be explored in the discovery of new therapeutic approaches for GC treatment. Keywords: ATP6AP2, Cell viability, Gastric cancer, miR-148a-3p, Progression

scholarly journals Voluntary Control of Auditory Hallucinations: Phenomenology to Therapeutic Implications

2019 ◽  
Author(s):  
Ariel Swyer ◽  
albert powers
Keyword(s):  
Health Status ◽  
Treatment Seeking ◽  
Therapeutic Approaches ◽  
Auditory Verbal Hallucinations ◽  
Therapeutic Implications ◽  
New Therapeutic Approaches ◽  
Key Factor ◽  
Neural Underpinnings ◽  
The Relationship ◽  
Conscious Control

Auditory verbal hallucinations (AVH) have traditionally been thought to be outside the influence of conscious control. However, recent work with voice-hearers makes clear that both treatment-seeking and non-treatment seeking voice-hearers may exert varying degrees of control over their voices. Evidence suggests that this ability may be a key factor in determining health status, but little systematic examination of control in AVH has been carried out. This review provides an overview of the research examining control over AVH in both treatment-seeking and non-treatment-seeking populations. We first examine the relationship between control over AVH and health status as well as the psychosocial factors that may influence control and functioning. We then link control to various cognitive constructs that appear to be important for voice-hearing. Finally, we reconcile the possibility of control with the field’s current understanding of the proposed cognitive, computational, and neural underpinnings of hallucinations and perception more broadly. Established relationships between control, health status, and functioning suggest that the development of control over AVH could increase functioning and reduce distress. A more detailed understanding of the discrete types of control, their development, and their neural underpinnings is essential for translating this knowledge into new therapeutic approaches.

scholarly journals Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Yu-chi Shen ◽  
Caroline Arellano-Garcia ◽  
Rosa E. Menjivar ◽  
Ethan M. Jewett ◽  
Wolfgang Dohle ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Lines ◽  
Tumour Cell ◽  
Mechanisms Of Action ◽  
Neurofibromatosis 1 ◽  
Tumour Suppressor ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Tumour Cell Lines

Abstract Background Neurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2. Methods STX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed. Results Although neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death. Conclusions Both STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.

scholarly journals Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 111 ◽  
Author(s):  
Melinda N. Tea ◽  
Santosh I. Poonnoose ◽  
Stuart M. Pitson
Keyword(s):  
Brain Tumor ◽  
Cell Signaling ◽  
Cellular Responses ◽  
Sphingolipid Metabolism ◽  
Structural Components ◽  
Therapeutic Approaches ◽  
Myelin Sheaths ◽  
New Therapeutic Approaches ◽  
The Brain

Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.

scholarly journals A.04 Functional investigations of CIC and ATXN1L in Oligodendroglioma

2017 ◽  
Vol 44 (S2) ◽  
pp. S9-S9
Author(s):  
D Wong ◽  
V LeBlanc ◽  
S Chittaranjan ◽  
S Chan ◽  
J Song ◽  
...  
Keyword(s):  
Cell Lines ◽  
Target Genes ◽  
Transcriptome Profiling ◽  
Clinical Samples ◽  
Therapeutic Approaches ◽  
Deletion Mutations ◽  
Protein Levels ◽  
Sirna Knockdown ◽  
The Relationship ◽  
Slow Growing

Background: Oligodendroglioma (ODG), a molecularly defined subtype of glioma, is a treatment responsive, slow growing tumour strongly associated with IDH mutation and 1p19q co-deletion. Mutations in Capicua (CIC), located on chromosome 19q, have been found in up to 70% of IDH mutated, 1p19q co-deleted ODGs; suggesting that loss or altered function of CIC may be crucially associated with ODG’s unique biology. CIC and ATXN1L have previously been implicated in neurodegeneration, however, this interaction has not been studied in cancer. Methods: Transcriptome profiling of CIC knockout HEK293 cell lines generated using CRISPR was performed using microarray. CIC and ATXN1L interaction was confirmed using immunoprecipitation and immunofluorescence. Transcript and protein changes of CIC targets were tested using RT-qPCR and Western blot following ATXN1L siRNA knockdown. Results: Transcriptomic profiling of CIC knockout cell lines resulted in a list of candidate CIC target genes validated against clinical samples. Immunoprecipitation and immunofluorescence confirmed CIC and ATXN1L interaction. Derepression of candidate CIC targets at transcript and protein levels was seen upon siRNA knockdown of ATXN1L. Conclusions: The interaction between CIC and ATXN1L is necessary for the repression of CIC target genes, including known oncogenes. Further research into the relationship between CIC and ATXN1L may lead potentially novel avenues of therapeutic approaches for less favorable gliomas.

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