scholarly journals Hypoxic Jumbo Spheroids On-A-Chip (HOnAChip): Insights into Treatment Efficacy

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4046
Author(s):  
Elena Refet-Mollof ◽  
Ouafa Najyb ◽  
Rodin Chermat ◽  
Audrey Glory ◽  
Julie Lafontaine ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Microenvironment ◽  
Cell Lines ◽  
Treatment Efficacy ◽  
Gold Standard ◽  
Soft Lithography ◽  
Sarcoma Cell ◽  
Hypoxic Tumor ◽  
Clinical Tools ◽  
User Friendly

Hypoxia is a key characteristic of the tumor microenvironment, too rarely considered during drug development due to the lack of a user-friendly method to culture naturally hypoxic 3D tumor models. In this study, we used soft lithography to engineer a microfluidic platform allowing the culture of up to 240 naturally hypoxic tumor spheroids within an 80 mm by 82.5 mm chip. These jumbo spheroids on a chip are the largest to date (>750 µm), and express gold-standard hypoxic protein CAIX at their core only, a feature absent from smaller spheroids of the same cell lines. Using histopathology, we investigated response to combined radiotherapy (RT) and hypoxic prodrug Tirapazamine (TPZ) on our jumbo spheroids produced using two sarcoma cell lines (STS117 and SK-LMS-1). Our results demonstrate that TPZ preferentially targets the hypoxic core (STS117: p = 0.0009; SK-LMS-1: p = 0.0038), but the spheroids’ hypoxic core harbored as much DNA damage 24 h after irradiation as normoxic spheroid cells. These results validate our microfluidic device and jumbo spheroids as potent fundamental and pre-clinical tools for the study of hypoxia and its effects on treatment response.

scholarly journals A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 128
Author(s):  
Lixia Chen ◽  
Yang Zhang ◽  
Xinming Zhang ◽  
Ruijuan Lv ◽  
Rongtian Sheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
X Ray ◽  
Cells In Culture ◽  
Ht29 Cells ◽  
Radiotherapy Field ◽  
Anticancer Treatment ◽  
Hypoxic Tumor

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

scholarly journals Identification of a Hypoxia-Related Molecular Classification and Hypoxic Tumor Microenvironment Signature for Predicting the Prognosis of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoli Sun ◽  
Huan Luo ◽  
Chenbo Han ◽  
Yu Zhang ◽  
Cunli Yan
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Molecular Classification ◽  
Hypoxic Tumor ◽  
Score Model ◽  
Prognostic Prediction

PurposeThe hypoxic tumor microenvironment was reported to be involved in different tumorigenesis mechanisms of triple-negative breast cancer (TNBC), such as invasion, immune evasion, chemoresistance, and metastasis. However, a systematic analysis of the prognostic prediction models based on multiple hypoxia-related genes (HRGs) has not been established in TNBC before in the literature. We aimed to develop and verify a hypoxia gene signature for prognostic prediction in TNBC patients.MethodsThe RNA sequencing profiles and clinical data of TNBC patients were generated from the TCGA, GSE103091, and METABRIC databases. The TNBC-specific differential HRGs (dHRGs) were obtained from differential expression analysis of hypoxia cultured TNBC cell lines compared with normoxic cell lines from the GEO database. Non-negative matrix factorization (NMF) method was then performed on the TNBC patients using the dHRGs to explore a novel molecular classification on the basis of the dHRG expression patterns. Prognosis-associated dHRGs were identified by univariate and multivariate Cox regression analysis to establish the prognostic risk score model.ResultsBased on the expressions of 205 dHRGs, all the patients in the TCGA training cohort were categorized into two subgroups, and the patients in Cluster 1 demonstrated worse OS than those in Cluster 2, which was validated in two independent cohorts. Additionally, the effects of somatic copy number variation (SCNV), somatic single nucleotide variation (SSNV), and methylation level on the expressions of dHRGs were also analyzed. Then, we performed Cox regression analyses to construct an HRG-based risk score model (3-gene dHRG signature), which could reliably discriminate the overall survival (OS) of high-risk and low-risk patients in TCGA, GSE103091, METABRIC, and BMCHH (qRT-PCR) cohorts.ConclusionsIn this study, a robust predictive signature was developed for patients with TNBC, indicating that the 3-gene dHRG model might serve as a potential prognostic biomarker for TNBC.

scholarly journals Eltrombopag inhibits the proliferation of Ewing sarcoma cells via iron chelation and impaired DNA replication

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Torin Waters ◽  
Kelli L. Goss ◽  
Stacia L. Koppenhafer ◽  
William W. Terry ◽  
David J. Gordon
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cell Lines ◽  
Ewing Sarcoma ◽  
Gene Knockout ◽  
Replication Stress ◽  
Sarcoma Cell ◽  
Thrombopoietin Receptor ◽  
Dna Replication Stress ◽  
Sarcoma Cells

Abstract Background The treatment of Ewing sarcoma, an aggressive bone and soft tissue sarcoma, is associated with suboptimal outcomes and significant side-effects. Consequently, there is an urgent need to identify novel therapies that will improve outcomes for children and adults with Ewing sarcoma tumors while also decreasing treatment-related toxicities. Methods We analyzed data from the PRISM drug repurposing screen, which tested the activity of 4518 drugs across 578 cancer cell lines, to identify drugs that selectively inhibit the growth of Ewing sarcoma cell lines. We then tested the effects of a top hit from the screen on cell proliferation, cell cycle progression, and activation of the DNA damage pathway using Ewing sarcoma cell lines. We also used a CRISPR/Cas9 gene knockout approach to investigate the role of Schlafen 11 (SLFN11), a restriction factor for DNA replication stress that is overexpressed in Ewing sarcoma tumors, in mediating the sensitivity of Ewing sarcoma cells to the drug. Results We found that eltrombopag, an FDA-approved thrombopoietin-receptor agonist (TPO-RA) that is currently being evaluated as a treatment for chemotherapy-induced thrombocytopenia, inhibits the growth of Ewing sarcoma cell lines in vitro in proliferation and colony formation assays. However, from a mechanistic standpoint, the thrombopoietin receptor is not expressed in Ewing sarcoma cells and we show that eltrombopag impairs DNA replication and causes DNA damage in Ewing sarcoma cells by chelating iron, a known “off-target” effect of the drug. We also found that the sensitivity of Ewing sarcoma cells to eltrombopag is mediated, in part, by SLFN11, which regulates the cellular response to DNA replication stress. Conclusions Ewing sarcoma cell lines are sensitive to eltrombopag and this drug could improve outcomes for patients with Ewing sarcoma tumors by both targeting the tumor, via chelation of iron and inhibition of DNA replication, and reducing chemotherapy-induced thrombocytopenia, via stimulation of the thrombopoietin receptor.

Chem-inspired hollow ceria nanozymes with lysosome-target for tumor synergistic phototherapy

2021 ◽  
Author(s):  
Li Zhou ◽  
Wei Li ◽  
Yilin Wen ◽  
Xiaoxue Fu ◽  
Feng Leng ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Treatment Efficacy ◽  
Innovative Approach ◽  
Improve Treatment ◽  
Hypoxic Tumor ◽  
Improve Treatment Efficacy

The precise operation of the hypoxic tumor microenvironment presents a promising way to improve treatment efficacy, especially in tumor synergistic phototherapy. This work reports an innovative approach to build adenosine...

Bestimmung der DNA-Schädigung in vitro

2010 ◽  
Vol 49 (S 01) ◽  
pp. S64-S68
Author(s):  
E. Dikomey
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Chromosome Aberrations ◽  
Genetic Factors ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Cell Inactivation ◽  
Repair Mechanisms ◽  
Break Repair

SummaryIonising irradiation acts primarily via induction of DNA damage, among which doublestrand breaks are the most important lesions. These lesions may lead to lethal chromosome aberrations, which are the main reason for cell inactivation. Double-strand breaks can be repaired by several different mechanisms. The regulation of these mechanisms appears be fairly different for normal and tumour cells. Among different cell lines capacity of doublestrand break repair varies by only few percents and is known to be determined mostly by genetic factors. Knowledge about doublestrand break repair mechanisms and their regulation is important for the optimal application of ionising irradiation in medicine.

scholarly journals PC12 and THP-1 Cell Lines as Neuronal and Microglia Model in Neurobiological Research

2021 ◽  
Vol 11 (9) ◽  
pp. 3729
Author(s):  
Katarzyna Balon ◽  
Benita Wiatrak
Keyword(s):  
Cell Culture ◽  
Dna Damage ◽  
Cell Lines ◽  
Inflammatory Factor ◽  
Research Model ◽  
Differentiated Cells ◽  
Undifferentiated Cells ◽  
Primary Cell Lines ◽  
Neurobiological Research ◽  
The Impact

Models based on cell cultures have become a useful tool in modern scientific research. Since primary cell lines are difficult to obtain and handle, neoplasm-derived lines like PC12 and THP-1 offer a cheap and flexible solution for neurobiological studies but require prior differentiation to serve as a neuronal or microglia model. PC12 cells constitute a suitable research model only after differentiation by incubation with nerve growth factor (NGF) and THP-1 cells after administering a differentiation factor such as phorbol 12-myristate-13-acetate (PMA). Still, quite often, studies are performed on these cancer cells without differentiation. The study aimed to assess the impact of PC12 or THP-1 cell differentiation on sensitivity to harmful factors such as Aβ25-35 (0.001–5 µM) (considered as one of the major detrimental factors in the pathophysiology of Alzheimer’s disease) or lipopolysaccharide (1–100 µM) (LPS; a pro-inflammatory factor of bacterial origin). Results showed that in most of the tests performed, the response of PC12 and THP-1 cells induced to differentiation varied significantly from the effect in undifferentiated cells. In general, differentiated cells showed greater sensitivity to harmful factors in terms of metabolic activity and DNA damage, while in the case of the free radicals, the results were heterogeneous. Obtained data emphasize the importance of proper differentiation of cell lines of neoplastic origin in neurobiological research and standardization of cell culture handling protocols to ensure reliable results.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

scholarly journals Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Kaili Long ◽  
Lili Gu ◽  
Lulu Li ◽  
Ziyu Zhang ◽  
Enjie Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Small Molecule ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Molecular Compound ◽  
Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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