scholarly journals KML001, a Telomere-Targeting Drug, Sensitizes Glioblastoma Cells to Temozolomide Chemotherapy and Radiotherapy through DNA Damage and Apoptosis

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Seon Rang Woo ◽  
Yunhee Ham ◽  
Wonyoung Kang ◽  
Heekyoung Yang ◽  
Sujong Kim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Synergistic Effects ◽  
Resistant Cell Line ◽  
Therapeutic Effects ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Cytotoxic Treatment ◽  
Xenograft Models

Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects onin vitrosurvival of glioblastoma cells, cell death byin vitrotemozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylatedγ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma.

scholarly journals The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3470
Author(s):  
Aubrey L. Miller ◽  
Patrick L. Garcia ◽  
Samuel C. Fehling ◽  
Tracy L. Gamblin ◽  
Rebecca B. Vance ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cholesterol Biosynthesis ◽  
Antitumor Efficacy ◽  
Rna Seq ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Xenograft Models

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

scholarly journals Genotoxic Effects of Green Tea Extract on Human Laryngeal Carcinoma Cells In Vitro

2011 ◽  
Vol 62 (2) ◽  
pp. 139-146 ◽  
Author(s):  
Ksenija Durgo ◽  
Sandra Kostić ◽  
Katarina Gradiški ◽  
Draženka Komes ◽  
Maja Osmak ◽  
...  
Keyword(s):  
Cell Line ◽  
Green Tea ◽  
Laryngeal Carcinoma ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Green Tea Extract ◽  
Carcinoma Cells ◽  
Tea Extract ◽  
Human Laryngeal Carcinoma

Genotoxic Effects of Green Tea Extract on Human Laryngeal Carcinoma Cells In VitroGreen tea (Camellia sinensis) contains several bioactive compounds which protect the cell and prevent tumour development. Phytochemicals in green tea extract (mostly flavonoids) scavenge free radicals, but also induce pro-oxidative reactions in the cell. In this study, we evaluated the potential cytotoxic and prooxidative effects of green tea extract and its two main flavonoid constituents epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) on human laryngeal carcinoma cell line (HEp2) and its cross-resistant cell line CK2. The aim was to see if the extract and its two flavonoids could increase the sensitivity of the cisplatin-resistant cell line CK2 in comparison to the parental cell line. The results show that EGCG and green tea extract increased the DNA damage in the CK2 cell line during short exposure. The cytotoxicity of EGCG and ECG increased with the time of incubation. Green tea extract induced lipid peroxidation in the CK2 cell line. The pro-oxidant effect of green tea was determined at concentrations higher than those found in traditionally prepared green tea infusions.

scholarly journals Silencing VEGF enhances the radiosensitivity of the radioresistant human nasopharyngeal carcinoma cell line CNE-2R by inhibiting autophagy through the activation of mTOR pathway

2020 ◽  
Author(s):  
Li Chen ◽  
Guoxiang Lin ◽  
Kaihua Chen ◽  
Fangzhu Wan ◽  
Yongchu Sun ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Carcinoma ◽  
Cell Line ◽  
Western Blotting ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Angiogenic Factor ◽  
Cell Counting

Abstract Background: Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced to the radioresistance of tumors. The purpose of our study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma radioresistant cell line CNE-2R and the underlying mechanisms.Methods: The radiosensitivity of CNE-2R cells after silencing VEGF was detected by cell counting kit 8 (CCK-8) and clonogenic assay, cell cycle and apoptosis was subjected to flow cytometry. DNA damage and autophagy were observed by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation analysis. In vivo, the effect of VEGF on radiosensitivity of NPC cells was investigated through xenograft model, furthermore, immunohistochemistry and TUNEL assay were used to further verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion.Results: Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of CNE-2R cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in CNE-2R cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through the activation of mTOR pathway.Conclusion: VEGF depletion increased radiosensitivity of NPC radioresistant cell CNE-2R by suppressing autophagy via the activation of mTOR pathway.

Epigenetic approaches to cancer therapy

2004 ◽  
Vol 32 (6) ◽  
pp. 1095-1097 ◽  
Author(s):  
J.A. Plumb ◽  
N. Steele ◽  
P.W. Finn ◽  
R. Brown
Keyword(s):  
Dna Methylation ◽  
Cell Line ◽  
Gene Promoter ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Tumour Suppressor Genes ◽  
Control Of Gene Expression ◽  
Hmlh1 Gene

Histone deacetylation and DNA methylation have a central role in the control of gene expression, including transcriptional repression of tumour suppressor genes. Loss of DNA mismatch repair due to methylation of the hMLH1 gene promoter results in resistance to cisplatin in vitro and in vivo. The cisplatin-resistant cell line A2780/cp70 is 8-fold more resistant to cisplatin than the non-resistant cell line, and has the hMLH1 gene methylated. Treatment with an inhibitor of DNA methyltransferase, DAC (2-deoxy-5′-azacytidine), results in a partial reversal of DNA methylation, re-expression of MLH1 (mutL homologue 1) and sensitization to cisplatin both in vitro and in vivo. PXD101 is a novel hydroxamate type histone deacetylase inhibitor that shows antitumour activity in vivo and is currently in phase I clinical evaluation. Treatment of A2780/cp70 tumour-bearing mice with DAC followed by PXD101 results in a marked increase in the number of cells that re-express MLH1. Since the clinical use of DAC may be limited by toxicity and eventual re-methylation of genes, we suggest that the combination of DAC and PXD101 could have a role in increasing the efficacy of chemotherapy in patients with tumours that lack MLH1 expression due to hMLH1 gene promoter methylation.

Is the natural PCDD/PCDF mixture toxic for human placental JEG-3 cell line? The action of the toxicants on hormonal profile, CYP1A1 activity, DNA damage and cell apoptosis

2007 ◽  
Vol 26 (5) ◽  
pp. 407-417 ◽  
Author(s):  
Katarzyna Augustowska ◽  
Zofia Magnowska ◽  
Maria Kapiszewska ◽  
Ewa L. Gregoraszczuk
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Cell Apoptosis ◽  
Hormone Production ◽  
Dna Migration ◽  
Extraction And Purification ◽  
Cyp1a1 Expression ◽  
Cross Links ◽  
Placental Hormone

The present study was conducted to define the action of a mixture obtained by the extraction and purification of real fly ash, on specific toxicity endpoints, such as hormonal secretion, CYP1A1 expression, DNA damage and cell apoptosis. JEG-3 cell line was exposed in vitro to different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or Polychlorinated dibenzo-p-dioxin/Polychlorinated dibenzo-P-furan (PCDD/PCDF) mixture. Both TCDD and the mixture decreased hCG secretion, while inhibition of progesterone levels was noted only under the influence of TCDD. The changes in hormone production were not due to the action on cell viability. There were time-dependent differences in CYP1A1 expression in cells exposed to TCDD and PCDD/PCDF mixture. Both TCDD and PCDD/PCDF mixture did not induce the DNA damage, as evaluated by the comet assay. Significantly lower DNA migration from the head of comet into the comet tail was noted after the removal of reagents. The highest efficiency of this process was noted 4 h after the TCDD and 24 h after the PCDD/PCDF mixture removal. These results suggest that the DNA adducts and/or DNA—DNA cross-links were formed. Neither TCDD nor PCDD/PCDF mixture had any effect on cell apoptosis assessed by caspase-3 activity and Hoechst 33258. Taken together, these findings clearly indicate a weaker action of the mixture when compared with TCDD. However, in both cases, their action was not due to the induction of the DNA damage and subsequent cell apoptosis but due to a direct influence of these toxicants on placental hormone production. Human & Experimental Toxicology ( 2007) 26, 407—417

CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 727-736 ◽  
Author(s):  
Cun Wang ◽  
Hui Wang ◽  
Cor Lieftink ◽  
Aimee du Chatinier ◽  
Dongmei Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

ObjectivesHepatocellular carcinoma (HCC) is one of the most frequent malignancies and a major leading cause of cancer-related deaths worldwide. Several therapeutic options like sorafenib and regorafenib provide only modest survival benefit to patients with HCC. This study aims to identify novel druggable candidate genes for patients with HCC.DesignA non-biased CRISPR (clustered regularly interspaced short palindromic repeats) loss-of-function genetic screen targeting all known human kinases was performed to identify vulnerabilities of HCC cells. Whole-transcriptome sequencing (RNA-Seq) and bioinformatics analyses were performed to explore the mechanisms of the action of a cyclin-dependent kinase 12 (CDK12) inhibitor in HCC cells. Multiple in vitro and in vivo assays were used to study the synergistic effects of the combination of CDK12 inhibition and sorafenib.ResultsWe identify CDK12 as critically required for most HCC cell lines. Suppression of CDK12 using short hairpin RNAs (shRNAs) or its inhibition by the covalent small molecule inhibitor THZ531 leads to robust proliferation inhibition. THZ531 preferentially suppresses the expression of DNA repair-related genes and induces strong DNA damage response in HCC cell lines. The combination of THZ531 and sorafenib shows striking synergy by inducing apoptosis or senescence in HCC cells. The synergy between THZ531 and sorafenib may derive from the notion that THZ531 impairs the adaptive responses of HCC cells induced by sorafenib treatment.ConclusionOur data highlight the potential of CDK12 as a drug target for patients with HCC. The striking synergy of THZ531 and sorafenib suggests a potential combination therapy for this difficult to treat cancer.

scholarly journals Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo

2010 ◽  
Vol 9 (11) ◽  
pp. 875-884 ◽  
Author(s):  
Lin Deng ◽  
Gang Li ◽  
Ronghui Li ◽  
Qinglin Liu ◽  
Qiaowei He ◽  
...  
Keyword(s):  
Cell Line ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Glioblastoma Cell Line ◽  
Glioblastoma Cell ◽  
Rho Kinase Inhibitor
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