scholarly journals CBIO-11. NOVEL THERAPY TO TARGET PR-RECURRENT GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii18
Author(s):  
Masum Rahman ◽  
Ian E Olson ◽  
Rehan Saber ◽  
Jibo Zhang ◽  
Lucas P Carlstrom ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Recurrence ◽  
Primary Brain Tumor ◽  
Differential Sensitivity ◽  
Proliferating Cells ◽  
Novel Therapy ◽  
Conventional Radiation ◽  
Long Time ◽  
Radiation Induced

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

Differential sensitivity of AS-30D rat hepatoma cells and normal hepatocytes to anoxic cell damage

1992 ◽  
Vol 262 (6) ◽  
pp. C1384-C1387 ◽  
Author(s):  
C. E. Kobryn ◽  
G. Fiskum
Keyword(s):  
Tumor Cells ◽  
Cell Damage ◽  
Metabolic Stress ◽  
Metastatic Potential ◽  
Cell Types ◽  
Hepatoma Cells ◽  
Differential Sensitivity ◽  
Trypan Blue Exclusion ◽  
Lactate Dehydrogenase Release

A substantial fraction of cells present within hard tumors experience extremely hypoxic and hypoglycemic conditions that can lead to phenotypic alterations such as increased metastatic potential and chemotherapeutic drug resistance. Little is known regarding the influence of anoxic aglycemia on tumor cell energy metabolism and viability, and no direct comparisons have been made between the effects of this form of metabolic stress on tumor cells and their tissue of origin. In this study, the effects of in vitro aglycemic incubation under N2 (with or without iodoacetate) on trypan blue exclusion, lactate dehydrogenase release, cell surface blebbing, ATP levels, and mitochondrial respiratory capacity of rat AS-30D ascites hepatoma cells and normal hepatocytes were measured. Under anoxic-aglycemic conditions, the period of incubation during which 50% viability was lost was 2 h for hepatocytes and 6-8 h for AS-30D cells. In contrast, the rate of anoxia-induced loss of ATP was comparable for the two cell types, and mitochondrial damage was actually accelerated in the tumor cells. These findings suggest that tumor cells are more resistant to anoxic cell death because of their greater ability to withstand deenergization and subcellular injury.

scholarly journals Identification of a novel population of muscle stem cells in mice

2002 ◽  
Vol 157 (5) ◽  
pp. 851-864 ◽  
Author(s):  
Zhuqing Qu-Petersen ◽  
Bridget Deasy ◽  
Ron Jankowski ◽  
Makato Ikezawa ◽  
James Cummins ◽  
...  
Keyword(s):  
Stem Cells ◽  
Normal Karyotype ◽  
Stem Cell Markers ◽  
Proliferating Cells ◽  
Dystrophic Muscle ◽  
Myogenic Cells ◽  
Hematopoietic Stem ◽  
Long Time

Three populations of myogenic cells were isolated from normal mouse skeletal muscle based on their adhesion characteristics and proliferation behaviors. Although two of these populations displayed satellite cell characteristics, a third population of long-time proliferating cells expressing hematopoietic stem cell markers was also identified. This third population comprises cells that retain their phenotype for more than 30 passages with normal karyotype and can differentiate into muscle, neural, and endothelial lineages both in vitro and in vivo. In contrast to the other two populations of myogenic cells, the transplantation of the long-time proliferating cells improved the efficiency of muscle regeneration and dystrophin delivery to dystrophic muscle. The long-time proliferating cells' ability to proliferate in vivo for an extended period of time, combined with their strong capacity for self-renewal, their multipotent differentiation, and their immune-privileged behavior, reveals, at least in part, the basis for the improvement of cell transplantation. Our results suggest that this novel population of muscle-derived stem cells will significantly improve muscle cell–mediated therapies.

scholarly journals The Selectivity for Tumor Cells of Nuclear-Directed Cytotoxic RNases Is Mediated by the Nuclear/Cytoplasmic Distribution of p27KIP1

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1319
Author(s):  
Glòria García-Galindo ◽  
Jessica Castro ◽  
Jesús Matés ◽  
Marlon Bravo ◽  
Marc Ribó ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Complex Disease ◽  
Antitumor Action ◽  
Ovarian Cancer Cells ◽  
Proliferating Cells ◽  
New Strategy ◽  
Localization Signal ◽  
Multiple Species

Although single targeted anti-cancer drugs are envisaged as safer treatments because they do not affect normal cells, cancer is a very complex disease to be eradicated with a single targeted drug. Alternatively, multi-targeted drugs may be more effective and the tumor cells may be less prone to develop drug resistance although these drugs may be less specific for cancer cells. We have previously developed a new strategy to endow human pancreatic ribonuclease with antitumor action by introducing in its sequence a non-classical nuclear localization signal. These engineered proteins cleave multiple species of nuclear RNA promoting apoptosis of tumor cells. Interestingly, these enzymes, on ovarian cancer cells, affect the expression of multiple genes implicated in metabolic and signaling pathways that are critic for the development of cancer. Since most of these targeted pathways are not highly relevant for non-proliferating cells, we envisioned the possibility that nuclear directed-ribonucleases were specific for tumor cells. Here, we show that these enzymes are much more cytotoxic for tumor cells in vitro. Although the mechanism of selectivity of NLSPE5 is not fully understood, herein we show that p27KIP1 displays an important role on the higher resistance of non-tumor cells to these ribonucleases.

PI3K-Akt signaling regulates basal, but MAP-kinase signaling regulates radiation-induced XRCC1 expression in human tumor cells in vitro

DNA Repair ◽  
2008 ◽  
Vol 7 (10) ◽  
pp. 1746-1756 ◽  
Author(s):  
M TOULANY ◽  
K DITTMANN ◽  
B FEHRENBACHER ◽  
M SCHALLER ◽  
M BAUMANN ◽  
...  
Keyword(s):  
Map Kinase ◽  
Tumor Cells ◽  
Human Tumor ◽  
Akt Signaling ◽  
Kinase Signaling ◽  
Human Tumor Cells ◽  
Map Kinase Signaling ◽  
Radiation Induced

scholarly journals In Vitro Glioblastoma Models: A Journey into the Third Dimension

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2449
Author(s):  
Mayra Paolillo ◽  
Sergio Comincini ◽  
Sergio Schinelli
Keyword(s):  
Tumor Cells ◽  
Single Cell Analysis ◽  
3D Models ◽  
Primary Brain Tumor ◽  
Molecular Features ◽  
Third Dimension ◽  
One Year ◽  
The Impact

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.

Radiation-Induced Changes in Gene-Expression Profiles for the SCC VII Tumor Cells Grown In Vitro and In Vivo

2006 ◽  
Vol 8 (7-8) ◽  
pp. 1263-1272 ◽  
Author(s):  
John A. Cook ◽  
Eric Y. Chuang ◽  
Mong-Hsun Tsai ◽  
Debbie Coffin ◽  
William Degraff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Radiation Induced ◽  
Induced Changes

scholarly journals Radiobiological effects of the alpha emitter Ra-223 on tumor cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kristina Bannik ◽  
Balázs Madas ◽  
Marco Jarzombek ◽  
Andreas Sutter ◽  
Gerhard Siemeister ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tumor Cells ◽  
Biological Effects ◽  
Tumor Cell Lines ◽  
Radiation Induced ◽  
Radiobiological Effects ◽  
Dose Dependent ◽  
Α Particles

AbstractTargeted alpha therapy is an emerging innovative approach for the treatment of advanced cancers, in which targeting agents deliver radionuclides directly to tumors and metastases. The biological effects of α-radiation are still not fully understood - partly due to the lack of sufficiently accurate research methods. The range of α-particles is <100 μm, and therefore, standard in vitro assays may underestimate α-radiation-specific radiation effects. In this report we focus on α-radiation-induced DNA lesions, DNA repair as well as cellular responses to DNA damage. Herein, we used Ra-223 to deliver α-particles to various tumor cells in a Transwell system. We evaluated the time and dose-dependent biological effects of α-radiation on several tumor cell lines by biological endpoints such as clonogenic survival, cell cycle distribution, comet assay, foci analysis for DNA damage, and calculated the absorbed dose by Monte-Carlo simulations. The radiobiological effects of Ra-223 in various tumor cell lines were evaluated using a novel in vitro assay designed to assess α-radiation-mediated effects. The α-radiation induced increasing levels of DNA double-strand breaks (DSBs) as detected by the formation of 53BP1 foci in a time- and dose-dependent manner in tumor cells. Short-term exposure (1–8 h) of different tumor cells to α-radiation was sufficient to double the number of cells in G2/M phase, reduced cell survival to 11–20% and also increased DNA fragmentation measured by tail intensity (from 1.4 to 3.9) dose-dependently. The α-particle component of Ra-223 radiation caused most of the Ra-223 radiation-induced biological effects such as DNA DSBs, cell cycle arrest and micronuclei formation, leading ultimately to cell death. The variable effects of α-radiation onto the different tumor cells demonstrated that tumor cells show diverse sensitivity towards damage caused by α-radiation. If these differences are caused by genetic alterations and if the sensitivity could be modulated by the use of DNA damage repair inhibitors remains a wide field for further investigations.

scholarly journals Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

2020 ◽  
Author(s):  
Minghui Zhao ◽  
Yiwei Wang ◽  
Yucui Zhao ◽  
Sijia He ◽  
Ruyi Zhao ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Caspase 3 ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Promoting Effect ◽  
Damage Response ◽  
Radiation Induced ◽  
Growth Promoting

Abstract Background: Radiotherapy is an effective treatment on non-small-cell lung cancer (NSCLC). However, radiation-induced dying tumor cells are postulated to generate potent growth signals to stimulate the repopulation of adjacent surviving tumor cells, which may promote tumor recurrence. We investigated the role of caspase-3-centered molecular mechanism in NSCLC repopulation after radiotherapy.Methods: The stable caspase-3 knockout (Casp3 KO) NSCLC cells were compared with wild-type cells for growth-promoting effect after radiotherapy using in vitro repopulation model. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay and luciferase reporter assay were used to identify the possible molecules and pathway. To elucidate the function of caspase-3 in tumor repopulation, a series of in vitro assays were performed with Casp3 KO NSCLC cells. Finally, tumor cell growth rate of Casp3 KO and wild-type tumor cells in vivo was tested using xenograft tumor assay and key proteins were further confirmed in tumor tissues with or without radiotherapy.Results: We found that radiation induced DNA damage response (DDR) and caspase-3 activation, as well as promoted tumor repopulation in NSCLC cells. Unexpectedly, depleting caspase-3 significantly attenuated ataxia-telangiectasia mutated kinase (ATM)/p53-mediated DDR via attenuating endonuclease G (EndoG) nuclear migration, thus decreasing the growth-promoting effect of irradiated dying cells. Moreover, we identified p53 as a regulator of the Cox-2/PGE2 axis, which was probably involved in caspase-3-centered tumor repopulation after radiotherapy. Additionally, depleting caspase-3 in NSCLC cells showed impaired tumor growth in nude mice model.Conclusions: Our findings demonstrated that caspase-3 was implicated in tumor repopulation and that was accompanied by promoting DDR and downstream Cox-2/PGE2 axis activation in NSCLC cells. This hitherto undescribed signaling pathway mediated by caspase-3 may deepen insight into the radiobiology and provide therapeutic targets to reduce NSCLC recurrence after radiotherapy.

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