1,721,188 research outputs found
Abstract 1095: A combination of suberoylanilide hydroxamic acid and quinacrine is an effective therapeutic approach in preclinical settings of upper gastrointestinal cancers
No full textAbstract
Background: Quinacrine (QC), an antimalarial drug, has been shown to possess anticancer effects. Suberoylanilide hydroxamic acid (SAHA) inhibits class I and class II HDACs and is approved for cancer therapy. Developing novel approaches to overcome cancer drug resistance could significantly enhance current therapeutic approaches and improve patient care.
Methods: ATP-GLO, clonogenic survival, Annexin-V apoptosis assay, comet assay and DNA double-strand breaks (DSB) kits were used. The mRNA and protein levels were evaluated by quantitative real-time PCR and Western blot analyses.
Results: A combination of QC/SAHA significantly increased cell death in all cancer cell lines and had no effect on immortalized non-cancer cell lines (HFE145, NIH-3T3 and EPC2) (P<0.01). Clonogenic survival assay indicated that QC/SAHA co-treatment led to significantly lower number of cancer cell colonies, as compared to single agents and controls (P<0.01). Of note, the QC/SAHA combination led to an increase in the the sub-G0 population in AGS (9-fold), MKN-28 (14-fold), FLO1 (5.6-fold), and SNU1 (4-fold) cells (P<0.01). These results were confirmed using the Annexin V apoptosis induced significantly higher levels of apoptosis (10 - 20 fold) as compared to single agent and control (P<0.01). Treatment with QC/SAHA combination induced high levels of DSB (>20 fold, P<0.01). Comet assay data showed increased DNA damage compared with vehicle-treated cells (8-fold, P<0.01). Western blot analysis demonstrated a notable increase in activation of PARP, caspases 3, 9 and γ-H2AX following QC/SAHA co-treatment in all cancer cell lines. Interestingly, the combination of QC/SAHA substantially decreased the protein levels of both wtP53 and mutP53 in these cells. Tumor xenograft data confirmed that a combination of QC/SAHA is more effective than a single agent in abrogating tumor growth (P<0.05).
Conclusion: Our novel findings show that QC and SAHA have a synergistic effect on cancer cell death. The results provide compelling evidence that increased DNA damage mediates the cytotoxic effect of combined QC/SAHA. Such effect is likely related to mutP53 and wtP53 protein degradation induced by QC/SAHA combination. Our findings provide a rationale for a clinical evaluation of combined QC/SAHA therapy in gastro-esophageal cancers. Ongoing studies are currently being undertaken to understand mechanisms that regulate the degradation of wtp53 and mutp53 proteins.
Citation Format: Shoumin Zhu, Wael El-Rifai. A combination of suberoylanilide hydroxamic acid and quinacrine is an effective therapeutic approach in preclinical settings of upper gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1095. doi:10.1158/1538-7445.AM2017-1095</jats:p
Optimizing Trabectedin Therapy for the Treatment of Ewing Sarcoma
No full textEwing sarcoma is a highly aggressive pediatric bone tumor that is characterized EWS/FLI1 transcription factor. Ewing sarcoma tumors require the continued activity of EWS/FLI1 to sustain a gene signature that promotes proliferation and blocks differentiation leading to tumorigenesis and disease progression. Inhibition of EWS/FLI1 activity is not compatible with cell proliferation, which creates an attractive drug target. While no EWS/FLI1 targeted therapies have been translated into the clinic, trabectedin has demonstrated activity in early phase clinical trials. In this report, we optimize trabectedin therapy for the treatment of Ewing sarcoma. We identify the mechanism by which trabectedin inhibits EWS/FLI1 activity and demonstrate that inhibition can be achieved at clinically relevant concentrations. We use this novel mechanism of action to further optimize the schedule of administration and show that maximum EWS/FLI1 inhibition is obtained following a short term, high concentration treatment with trabectedin. Additionally, we characterize a second-generation analog of trabectedin, lurbinectedin, which has an improved pharmacokinetic profile that allows much higher serum concentrations to be achieved. In addition to being a bonafide EWS/FLI1 inhibitor, lurbinectedin can be combined with SN38 (in vitro) or irinotecan (in vivo) to augment the suppression of EWS/FLI1 target genes. Ultimately, we show that this combination strategy decreases tumor growth, extends lifespan, and leads to the differentiation of xenograft mouse models of Ewing sarcoma
Abstract 5482: Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival
No full textAbstract
Background: Esophageal adenocarcinoma (EAC) is the major type of malignant cancer of esophagus in the USA. The incidence rate has increased 4-10% per year among men since 1976 in the USA, more rapidly than for any other type of cancer. EAC is known to originate from premalignant Barrett’s esophagus (BE) through BE-dysplasia-EAC process. Normal cells have intact anti-oxidative mechanisms, among which NFE2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular response to various stimuli. Cancer cells have high levels of reactive oxygen species and oxidative stress due to activation of oncogenes, inflammatory microenvironment, and dysfunction of anti-oxidative mechanisms. However, the role of NRF2 in Barrett’s related esophageal carcinogenesis is barely known.
Methods and Results: We have found that Nrf2 protein expression is significantly upregulated in EAC cell lines as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines. We detected a similar overexpression of NRF2 in primary EAC tissue samples. Using luciferase reporter assay, we demonstrated significant induction of NRF2 transcription activity in EAC cells in response to exposure to acidic bile acids, as compared to controls (P&lt;.01). We detected significant increase in the expression of Heme Oxygenase 1 (HO-1) and Glutathione Reductase (GR) in these cells (P&lt;.01). Knockdown of NRF2 by siRNA or crisp/cas9, significantly increased cellular ROS level, oxidative DNA damage (8-oxoguanine), and double strand DNA breaks (p-H2AX). Knockdown of NRF2 sensitized cells to apoptosis following exposure to bile acids and CDDP. Concordant with these results, the use of NRF2 inhibitor, Brusatol, sensitized EAC cells to CDDP treatment with a significant increase in cell death, as compared to single agent treatment (P&lt;.01). Conclusion: These results indicate that constitutive overexpression of NRF2 in EAC cells protects cancer cells from high level of ROS and promotes cancer cell survival. Inhibition of NRF2 through its specific inhibitor may have therapeutic value in EAC.
Citation Format: Dunfa Peng, Tianling Hu, Shoumin Zhu, Wael El-Rifai. Constitutive overexpression of nrf2 in esophageal adenocarcinoma protects cancer cells from bile salts-induced DNA damage and favors cancer cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5482. doi:10.1158/1538-7445.AM2017-5482</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
The Role of Toll-Like Receptor 9 in Helicobacter pylori-Mediated Inflammation and Carcinogenesis
No full textCANCER BIOLOGY
The Role of Toll-Like Receptor 9 in Helicobacter pylori-Mediated
Inflammation and Carcinogenesis
Matthew Gordon Varga
Dissertation under the direction of Dr. Richard M. Peek Jr., MD
Helicobacter pylori is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. The H. pylori cag pathogenicity island encodes a type IV secretion system (T4SS), which translocates the pro-inflammatory protein CagA into host cells. Although T4SSs are ubiquitous and facilitate transport of diverse effectors from bacterial cells to the eukaryotic host, only two bacterial species have been shown to translocate DNA into eukaryotic host cells. Furthermore, in DNA-translocating T4SSs, the only proteins transported via the T4SS are proteins associated with the process of DNA transfer. Toll-like receptor 9 is an endosome bound, innate immune receptor that detects hypomethylated CpG DNA motifs. We now demonstrate that the H. pylori cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Genetic deficiency of Tlr9 augments the intensity of IL-17-driven immune responses to H. pylori in vivo, suggesting that engagement of TLR9 by bacterial DNA leads to suppression of inflammation, which may accommodate long-term interactions between pathogenic H. pylori and the gastric epithelium. In support of this hypothesis, analysis of a human population at increased risk for gastric cancer revealed that levels of H. pylori-mediated TLR9 activation were directly related to the severity of cancer risk. These results demonstrate the ever-increasing versatility of T4SS machineries and their involvement in promoting pathogen persistence and modulating disease outcomes
Delineation of signaling pathways induced by Helicobacter pylori that regulate host cell survival
No full textGastric adenocarcinoma is strongly associated with the presence of H. pylori. Microbial factors of H. pylori and host responses induced by the interactions of H. pylori with gastric epithelial cells play important roles in the development of disease. PI3K and β-catenin/p120 are multifunctional host proteins that coordinate carcinogenic epithelial responses when aberrantly activated, such as in malignant gastric lesions. We demonstrate that H. pylori infection results in upregulation of PI3K-AKT signaling, through stimulation of EGFR. Activation of this pathway reduces rates of epithelial cell death induced by H. pylori and promotes resistance to apoptosis. We also demonstrate that H. pylori infection induces additional host signaling pathways to potentiate a proliferative response in gastric epithelial cells. Specifically, PPARδ, a target of β-catenin transcriptional activation, contributes to increased rates of gastric epithelial cell proliferation in response to H. pylori infection. Based on these findings we hypothesize that an anti-apoptotic response in the presence of increased proliferation increases the risk of retaining mutagenized gastric epithelial cells in the presence of H. pylori induced gastritis. Taken together, these studies have identified effectors that directly mediate host responses related to carcinogenesis. Molecular delineation of such pathways activated by host-microbial interactions will improve our understanding of H. pylori-induced carcinogenesis, allowing for targeted therapies to high-risk individuals, as well as provide insight into other malignancies that arise within the context of pathogen-induced inflammation
The Role of Toll-Like Receptor 9 in Helicobacter pylori-Mediated Inflammation and Carcinogenesis
No full textDelineation of signaling pathways induced by Helicobacter pylori that regulate host cell survival
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